The Innate Immune System in Acute and Chronic Wounds

May combine two claims.

Symbiotic microorganisms occupy a wide range of skin niches and protect against invasion by more pathogenic or harmful organisms.

“Symbiotic microorganisms occupy a wide range of skin niches and protect against invasion by more pathogenic or harmful organisms.”

May combine two claims.

Consequently, the wound does not heal, but forms an ulcer that can last for years.

“Consequently, the wound does not heal, but forms an ulcer that can last for years.”

May combine two claims.

Commensal organisms such as strains of Staphylococcus epidermidis found in the skin secrete antibacterial compounds such as phenol-soluble modulins and interact with the host to induce AMP expression or reduce inflammation.

“Commensal organisms such as strains of Staphylococcus epidermidis found in the skin secrete compounds that are themselves antibacterial, such as phenol-soluble modulins,4,5 and also interact with the host to induce AMP expression6 or reduce inflammation.6”

• cites [4] Cogen A, Yamasaki K, Sanchez K, et al. Selective antimicrobial action is provided by phenol-soluble modulins derived from staphylococcus epidermidis, a normal resident of the skin. J Invest Dermatol 2010; 130: 192– 200 19710683 PMC2796468 sourceNot checked yet

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• cites [5] Cogen A, Yamasaki K, Muto J, et al. Staphylococcus epidermidis antimicrobial delta-toxin (phenol-soluble modulin-gamma) cooperates with host antimicrobial peptides to kill group A Streptococcus. PLoS One 2010; 5: e8557 20052280 PMC2796718 sourceNot checked yet

  Not checked in the free run.

• cites [6] Lai Y, Cogen AL, Radek KA, et al. Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. J Invest Dermatol 2010; 130: 2211– 2221 20463690 PMC2922455 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Bacterial products stimulate the innate immune system and play a role in the inception of inflammation, and commensal skin bacteria invade and become pathogenic upon breach of the skin barrier.

“Bacterial products stimulate the innate immune system and thus play a role in the inception of inflammation, and commensal skin bacteria invade and become pathogenic upon breach of the skin barrier.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

In normal skin, stable homeostasis and barrier function are established by interaction of resident keratinocytes, dendritic cells, T cells, mast cells, fibroblasts, and macrophages with each other and with the resident microbiome.

“In normal skin, stable homeostasis and barrier function are established by interaction of resident keratinocytes, dendritic cells (DCs), T cells, mast cells, fibroblasts, and macrophages with each other and with the resident microbiome.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Each stage of wound healing is activated by a series of cytokines and other mediators, which are, in part, released as the stage before approaches completion.

“Each stage is activated by a series of cytokines and other mediators, which are, in part, released as the stage before approaches completion.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Early local inflammatory mediators in the wound bed function as an immunological vehicle to facilitate immune cell infiltration and microbial clearance upon injury to the skin barrier.

“It is well established and accepted that early local inflammatory mediators in the wound bed function as an immunological vehicle to facilitate immune cell infiltration and microbial clearance upon injury to the skin barrier.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Human skin is colonized by a diverse skin microbiome.

“Human skin is colonized by a diverse skin microbiome.”

Probably not a substantial claim: may not pass S4 (based).

The normal relationship between commensal bacteria that interact with the innate immune system and the cells of the skin is extensively modified in chronic wounds.

“This relationship is extensively modified in chronic wounds.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The composition of the skin microflora varies in different regions of the body and, to lesser degrees, in different individuals and from time to time.

“The composition of the skin microflora varies in different regions of the body and, to lesser degrees, in different individuals and from time to time.8”

• cites [8] Huse SM, Ye Y, Zhou Y, Fodor AA A core human microbiome as viewed through 16S rRNA sequence clusters. PLoS One 2012; 7: 13 PMC3374614 22719824 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The innate immune system comprises a diverse range of defense systems that act to provide primary protection against harmful agents.

“The innate immune system comprises a diverse range of defense systems that act to provide primary protection against the harmful agents.”

May combine two claims.

The arrested stage in chronic wounds does not adequately pass on the signals for wound closure, but instead sets up a quasistable equilibrium with resident bacteria.

“The arrested stage does not adequately pass on the signals for wound closure, but instead sets up a quasistable equilibrium with resident bacteria.”

May combine two claims.

Chronic wounds fail to complete the initial clearance of microbial contamination by the innate immune system and stall in a late stage of the inflammatory process.

“This review discusses the basis for the development of chronic wounds that fail to complete the initial clearance of microbial contamination by the innate immune system and stall in a late stage of the inflammatory process.”

Probably not a substantial claim: may not pass S4 (based).

The early inflammatory stage of wound healing is the province of the innate immune system.

“The early inflammatory stage of wound healing is the province of the innate immune system.”

• Also stated in: § Background · plain

  “This inflammatory stage of wound healing is the province of the innate immune system.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The innate immune system interacts and instructs the adaptive immune system to elicit optimal immune responses.

“The innate immune system interacts and instructs the adaptive immune system to elicit optimal immune responses, as recently discussed.2”

• cites [2] Strbo N, Yin N, Stojadinovic O Innate and adaptive immune responses in wound epithelialization. Adv Wound Care (New Rochelle) 2014; 3: 492– 501 25032069 PMC4086194 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The innate immune system is capable of very rapid activation and deployment in response to pathogen-associated molecular patterns or danger-associated molecular patterns through Toll-like receptor systems and other innate immune receptors.

“The innate immune system is capable of very rapid activation and deployment in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) through the Toll-like receptor (TLR) systems and other innate immune receptors to recognize viruses, bacteria, endogenous or exogenous danger signals, or foreign particles.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Many skin microorganisms are harmless.

“Many of these skin microorganisms are harmless.”

May combine two claims.

AMP expression is highly dependent on the cytokine milieu present in the skin and proinflammatory cytokines such as IL-1, IL-6, IL-8, and TNFα are typically strong inducers of AMPs, whereas IL-4, IL-13, and IL-10 have been shown to dampen AMP responses.

“AMP expression is highly dependent on the cytokine milieu present in the skin and proinflammatory cytokines, such as IL-1, IL-6, IL-8, and tumor necrosis factor α (TNFα), are typically strong inducers of AMPs, whereas IL-4, IL-13, and IL-10 have been shown to dampen AMP responses.33–35”

• cites [33] Buchau AS EGFR (trans)activation mediates IL-8 and distinct human antimicrobial peptide and protein production following skin injury. J Invest Dermatol 2011; 130: 929– 932 20231833 sourceNot checked yet

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• cites [34] Howell MD, Boguniewicz M, Pastore S, et al. Mechanism of HBD-3 deficiency in atopic dermatitis. Clin Immunol 2006; 121: 332– 338 17015038 sourceNot checked yet

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• cites [35] Howell MD, Novak N, Bieber T, et al. Interleukin-10 downregulates anti-microbial peptide expression in atopic dermatitis. J Invest Dermatol 2005; 125: 738– 745 16185274 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Many AMPs are small cationic peptides binding to and interacting with the negatively charged membranes of microbes and are thereby able to kill the microbe through membrane disruption, whereas other AMPs inhibit bacterial metabolism or growth.

“Many AMPs are small cationic peptides binding to and interacting with the negatively charged membranes of microbes and are thereby able to kill the microbe through membrane disruption, whereas other AMPs inhibit bacterial metabolism or growth.31,32”

• cites [31] Brogden KA Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 2005; 3: 238– 250 15703760 sourceNot checked yet

  Not checked in the free run.

• cites [32] Glaser R, Harder J, Lange H, Bartels J, Christophers E, Schroder JM Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol 2005; 6: 57– 64 15568027 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

The importance of inflammation is believed to lie in the clearance of contaminating microorganisms.

“The importance of inflammation is believed to lie in the clearance of contaminating microorganisms.”

May combine two claims.

High abundance of miRNA-21 has been associated with accelerated conversion to M2-like macrophages, leading to the paradox that despite increases in inflammatory M1 macrophages, large numbers of M2-like macrophages are generated prematurely.

“However, high abundance of miRNA-21 has been associated with accelerated conversion to M2-like macrophages, leading to the paradox that despite increases in inflammatory M1 macrophages, large numbers of M2-like macrophages are generated prematurely.”

May combine two claims.

Suction blister wounds, where the blister roof is still intact, do not show substantial inflammation, whereas excisional wounds, ultraviolet-induced skin damage, superficial tape stripping or chemical skin irritants, and contact sensitizers cause inflammatory infiltrates.

“Interestingly, suction blister wounds, where the blister roof is still intact, do not show substantial inflammation,9 whereas excisional wounds, ultraviolet (UV)-induced skin damage, superficial tape stripping or chemical skin irritants, and contact sensitizers cause inflammatory infiltrates,17,23–26”

• cites [9] Reusch MK, Mansbridge JN, Nickoloff BJ, Morhenn VB Immunophenotyping of skin cells during healing of suction blister injury. Dermatologica 1991; 183: 179– 183 1683839Not checked yet

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• cites [17] Dorschner RA, Pestonjamasp VK, Tamakuwala S, et al. Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J Invest Dermatol J 2001; 117: 91– 97 11442754 sourceNot checked yet

  Not checked in the free run.

• cites [23] Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007; 449: 564– 569 17873860 sourceNot checked yet

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• cites [24] Nielsen MM, Lovato P, MacLeod AS, et al. IL-1beta-dependent activation of dendritic epidermal T cells in contact hypersensitivity. J Immunol 2014; 192: 2975– 2983 24600030 PMC4020443 sourceNot checked yet

  Not checked in the free run.

• cites [25] MacLeod AS, Hemmers S, Garijo O, et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J Clin Invest 2013; 123: 4364– 4374 24051381 PMC3784546 sourceNot checked yet

  Not checked in the free run.

• cites [26] Wilmer JL, Burleson FG, Kayama F, Kanno J, Luster MI Cytokine induction in human epidermal keratinocytes exposed to contact irritants. J Invest Dermatol 1994; 102: 915– 922 8006454 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The species composition of the bacterial communities in chronic wounds may differ from normal skin, but presumably also show species similarities and may persist for many years.

“The species composition of the bacterial communities in chronic wounds may differ from normal skin, but presumably also show species similarities and may persist for many years.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Cathelicidins are produced by neutrophils, keratinocytes, and other cells.

“Cathelicidins are produced by neutrophils, keratinocytes, and other cells.”

Probably not a substantial claim: may not pass S4 (based).

Upon skin injury, the innate immune system becomes rapidly activated.

“Upon skin injury, the innate immune system becomes rapidly activated.”

May combine two claims.

Recent mouse studies revealed that murine β-defensin 3 and Reg3γ, but not S100A8, have wound healing-promoting properties as they could rescue defective wound healing in IL-17A−/− mice, which show defective AMP induction.

“In fact, recent mouse studies further revealed that murine β-defensin 3 (the ortholog of hBD2) and Reg3γ (ortholog of REG3A), but not S100A8, have wound healing-promoting properties as they could rescue defective wound healing in IL-17A−/− mice, which show defective AMP induction.6,30”

• cites [6] Lai Y, Cogen AL, Radek KA, et al. Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. J Invest Dermatol 2010; 130: 2211– 2221 20463690 PMC2922455 sourceNot checked yet

  Not checked in the free run.

• cites [30] MacLeod AS, Rudolph R, Corriden R, Ye I, Garijo O, Havran WL Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair. J Immunol 2014; 192: 5695– 5702 24808367 PMC4048764 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

β-defensins have a relatively broad spectrum of antibacterial activity toward gram-positive bacteria and enhance inflammation by recruiting immune cells to the wound site through their chemoattractive properties.

“β-defensins also have a relatively broad spectrum of antibacterial activity toward gram-positive bacteria and enhance inflammation by recruiting immune cells to the wound site through their chemoattractive properties.”

May combine two claims.

Early events in the innate immune response to skin injury include the recruitment of neutrophils and the induction of antimicrobial peptides, particularly cathelicidin LL-37 in humans.

“Early events in the innate immune response to skin injury include the recruitment of neutrophils and the induction of antimicrobial peptides, particularly, in humans, the cathelicidin LL-37.17”

• cites [17] Dorschner RA, Pestonjamasp VK, Tamakuwala S, et al. Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J Invest Dermatol J 2001; 117: 91– 97 11442754 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

IL-17 and IL-22 are derived from skin-resident T cells and their activation is enhanced through purinergic signals, such as through extracellular adenosine triphosphate.

“IL-17 and IL-22 are derived from skin-resident T cells and their activation is enhanced through purinergic signals, such as through extracellular adenosine triphosphate (eATP).”

May combine two claims.

In addition to their antimicrobial functions, AMPs regulate keratinocyte growth and differentiation, cytokine production, and influence adaptive immunity.

“In addition to their antimicrobial functions, AMPs also regulate keratinocyte growth and differentiation, cytokine production, and influence adaptive immunity.25,27,28”

• cites [25] MacLeod AS, Hemmers S, Garijo O, et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J Clin Invest 2013; 123: 4364– 4374 24051381 PMC3784546 sourceNot checked yet

  Not checked in the free run.

• cites [27] Braff MH, Gallo RL Antimicrobial peptides: an essential component of the skin defensive barrier. Curr Top Microbiol Immunol 2006; 306: 91– 110 16909919Not checked yet

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• cites [28] Lai Y, Li D, Li C, et al. The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. Immunity 2012; 37: 74– 84 22727489 PMC3828049 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

These processes are regulated, at least in part, by S100 proteins and through TNFSF12, recently shown to be induced by IL-17 signaling.

“These processes are regulated, at least in part, by S100 proteins and through TNFSF12, recently shown to be induced by IL-17 signaling.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

S100A7 and S100A8/A9 have antimicrobial activity toward gram-positive and gram-negative bacteria.

“S100A7 and S100A8/A9 have antimicrobial activity toward gram-positive and gram-negative bacteria.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Keratinocyte apoptosis and differentiation are critical to epithelial remodeling and reestablishing the skin barrier.

“In addition, keratinocyte apoptosis and differentiation are critical to epithelial remodeling and reestablishing the skin barrier.”

May combine two claims.

In addition to their well-known role as effectors of innate immunity by killing microbes, AMPs have additional roles as proteinase inhibitors, chemokines, neuropeptides, and in vascularization, which may contribute to their broad function in wound repair.

“In addition to their well-known role as effectors of innate immunity by killing microbes, AMPs have additional roles as proteinase inhibitors, chemokines, neuropeptides, and in vascularization, which may contribute to their broad function in wound repair.27”

• cites [27] Braff MH, Gallo RL Antimicrobial peptides: an essential component of the skin defensive barrier. Curr Top Microbiol Immunol 2006; 306: 91– 110 16909919Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Inflammation may involve cells such as macrophages, neutrophils, proinflammatory cytokines, vasoactive amines, reactive oxygen species, nitric oxide, extracellular adenosine triphosphate, double-stranded ribonucleic acid, hyaluronic acid, uric acid, eicosanoids, AMPs, and other mediators, which create, trigger, or amplify skin inflammatory responses.

“Inflammation may involve cells, such as macrophages, neutrophils, proinflammatory cytokines, vasoactive amines, reactive oxygen species (ROS), NO, extracellular adenosine triphosphate (eATP), double-stranded ribonucleic acid (dsRNA), hyaluronic acid, uric acid, eicosanoids, AMPs, and other mediators, which in concert create, trigger, or amplify skin inflammatory responses.”

May combine two claims.

If biofilms occur, these microbes change their metabolism and a new ecology is set up with a modified microbiome.

“If this occurs, these microbes change their metabolism11 and a new ecology is set up with a modified microbiome.12,13”

• cites [11] Sauer K, Camper AK, Ehrlich GD, Costerton JW, Davies DG Pseudomonas aeruginosa displays multiple phenotypes during development as a biofilm. J Bacteriol 2002; 184: 1140– 1154 11807075 PMC134825 sourceNot checked yet

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• cites [12] Imirzalioglu C, Sethi S, Schneider C, et al. Distinct polymicrobial populations in a chronic foot ulcer with implications for diagnostics and anti-infective therapy. BMC Res Notes 2014; 7: 1756 PMC3974921 24679105 sourceNot checked yet

  Not checked in the free run.

• cites [13] Gontcharov V, Youn E, Sun Y, Wolcott RD, Dowd SE A comparison of bacterial composition in diabetic ulcers and contralateral intact skin. Open Microbiol J 2010; 4: 8– 19 20461221 PMC2866239 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Diabetes is associated with a chronic inflammatory state, which leads ultimately to an imbalance and dysregulation of skin immune function.

“Diabetes is associated with a chronic inflammatory state, which leads ultimately to an imbalance and dysregulation of skin immune function.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Cathelicidin acts not only as a potent antimicrobial agent to kill gram-positive bacteria but also serves immunomodulatory functions and can perpetuate inflammation.

“Cathelicidin acts not only as a potent antimicrobial agent to kill gram-positive bacteria but it also serves immunomodulatory functions and can perpetuate inflammation.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

High glucose levels are associated with high levels of AGE products ultimately enhancing vascular NO synthase inhibitor, thereby inhibiting NO production.

“High glucose levels are associated with high levels of AGE products ultimately enhancing vascular NO synthase inhibitor, thereby inhibiting NO production.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Healthy mammalian skin comprises cells and molecules that are poised to provide a first line of defense against microbial pathogens and to increase immunity in response to tissue injury or microbial threats.

“Healthy mammalian skin comprises cells and molecules that are poised to provide a first line of defense against microbial pathogens and to increase immunity in response to tissue injury or microbial threats.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

AMPs provide a soluble barrier that forms a strong impediment to microbial invasion.

“AMPs provide a soluble barrier that forms a strong impediment to microbial invasion.”

May combine two claims.

AMPs such as hBD1 and S100A7, S100A8, and S100A9 proteins are present under homeostatic conditions, whereas other AMPs such as cathelicidin, hBD2, hBD3, and REG3A require induction through environmental or endogenous triggers.

“AMPs, such as hBD1 and S100A7, S100A8, and S100A9 proteins, are present under homeostatic conditions, whereas other AMPs, such as cathelicidin, hBD2, hBD3, and regenerating islet-derived protein 3A (REG3A), require induction through environmental or endogenous triggers.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

TLR activation-induced CYP27B1 expression converts inactive 24D3 to 1.25D3, which is a strong inducer of cathelicidin antimicrobial peptide.

“TLR activation-induced CYP27B1 expression converts inactive 24D3 to 1.25D3, which is a strong inducer of cathelicidin antimicrobial peptide.”

Classified as probably not a substantial claim. May combine two claims.

Upon skin injury, the protective skin barrier is breached and the skin becomes more vulnerable to invasion of microbes.

“Upon skin injury, the protective skin barrier is breached and the skin becomes more vulnerable to invasion of microbes.”

May combine two claims.

Bacterial colonization does not necessarily cause inflammation, but high endotoxin levels and other microbial products can drive inflammatory responses.

“Bacterial colonization does not necessarily cause inflammation,6,19,20 but high endotoxin levels and other microbial products can drive inflammatory responses.”

• cites [6] Lai Y, Cogen AL, Radek KA, et al. Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. J Invest Dermatol 2010; 130: 2211– 2221 20463690 PMC2922455 sourceNot checked yet

  Not checked in the free run.

• cites [19] Farrar D Advanced Wound Repair Therapies. Philadelphia: Woodhead Publishing, 2010 sourceNot checked yet

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• cites [20] Lai Y, Di Nardo A, Nakatsuji T, et al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat Med 2009; 15: 1377– 1382 19966777 PMC2880863 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

miRNA-21 inhibits growth factor signaling by yet undefined mechanisms and delays wound closure.

“In addition, miRNA-21 inhibits growth factor signaling by yet undefined mechanisms and delays wound closure.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Many S100 proteins are overexpressed in skin cancer, metastasis, psoriasis, arthritis, wound healing, and inflammation.

“Many S100 proteins are overexpressed in skin cancer, metastasis, psoriasis, arthritis, wound healing, and inflammation.45”

• cites [45] Buchau AS, Hassan M, Kukova G, et al. S100A15, an antimicrobial protein of the skin: regulation by E. coli through Toll-like receptor 4. J Invest Dermatol 2007; 127: 2596– 2604 17625598Not checked yet

  Not checked in the free run.

May combine two claims.

Cathelicidin is low in venous leg ulcers and absent at the margin of other nonhealing wounds.

“Cathelicidin is low in venous leg ulcers and absent at the margin of other nonhealing wounds.29”

• cites [29] Heilborn JD, Nilsson MF, Kratz G, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol 2003; 120: 379– 389 12603850 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Cathelicidin is derived from a precursor molecule called human cathelicidin antimicrobial protein (hCAP18) that can release an antimicrobial peptide after cleavage.

“Similar to defensins, cathelicidin is derived from a precursor molecule called human cathelicidin antimicrobial protein (hCAP18) that can release an antimicrobial peptide after cleavage.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

In the early stages of normal wound healing, innate immune cells produce proinflammatory cytokines that exacerbate host defense functions by inducing antimicrobial molecules, attracting leukocytes, and creating an environment to protect from microbial infection.

“In the early stages of normal wound healing, innate immune cells produce proinflammatory cytokines that exacerbate host defense functions by inducing antimicrobial molecules, attracting leukocytes, and creating an environment to protect from microbial infection.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The majority of S100 genes are located within the epidermal differentiation complex on chromosome 1.q21, and 13 S100 proteins are expressed in normal and/or diseased epidermis.

“The majority of S100 genes are located within the epidermal differentiation complex on chromosome 1.q21, and 13 S100 proteins are expressed in normal and/or diseased epidermis.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

S100 proteins comprise a large family of low-molecular-weight proteins that are characterized by the presence of calcium-binding EF-hands.

“S100 proteins comprise a large family of low-molecular-weight proteins that are characterized by the presence of calcium-binding EF-hands.”

May combine two claims.

hBD2 expression is induced by high calcium concentrations and 1,25 vitamin D3.

“Furthermore, hBD2 expression is induced by high calcium concentrations and 1,25 vitamin D3.36”

• cites [36] Buchau AS, Gallo RL Innate immunity and antimicrobial defense systems in psoriasis. Clin Dermatol 2007; 25: 616– 624 18021900 PMC2699547 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

IL-1 expression is rapidly induced upon skin injury and is a key player in the wound response by amplifying inflammatory mediators.

“IL-1 expression is rapidly induced upon skin injury and is a key player in the wound response by amplifying inflammatory mediators.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Cathelicidin LL-37 is the best studied cathelicidin peptide in man, whereas in mice, Camp refers to the gene encoding cathelicidin-related antimicrobial peptide (CRAMP).

“Cathelicidin LL-37 is the best studied cathelicidin peptide in man, whereas in mice, Camp refers to the gene encoding cathelicidin-related antimicrobial peptide (CRAMP).”

May combine two claims.

CXCR2−/− mice display impaired neutrophil recruitment and delayed wound healing.

“CXCR2−/− mice display impaired neutrophil recruitment and delayed wound healing.47,48”

• cites [47] Devalaraja RM, Nanney LB, Du J, et al. Delayed wound healing in CXCR2 knockout mice. J Invest Dermatol 2000; 115: 234– 244 10951241 PMC2664868 sourceNot checked yet

  Not checked in the free run.

• cites [48] Milatovic S, Nanney LB, Yu Y, White JR, Richmond A Impaired healing of nitrogen mustard wounds in CXCR2 null mice. Wound Repair Regen 2003; 11: 213– 219 12753603 PMC2667443 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

IL-1β is a key inducer of the antimicrobial response in the skin and is also involved in shaping adaptive T cell immune responses.

“IL-1β is a key inducer of the antimicrobial response in the skin and is also involved in shaping adaptive T cell immune responses.”

May combine two claims.

In the skin, hBD1 is constitutively expressed, whereas hBD2 and hBD3 are highly upregulated upon wounding.

“In the skin, hBD1 is constitutively expressed, whereas hBD2 and hBD3 are highly upregulated upon wounding.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

They produce large amounts of cytokines to initiate and regulate inflammation.

“They produce large amounts of cytokines to initiate and regulate inflammation.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

IL-8 (CXCL8) is one of a group of chemokines, including CXCL1, 2, 3, 5, 6, and 8, that are neutrophil chemokines through a high-affinity receptor, CXCR2, and neutrophil activators through a low-affinity receptor, CXCR1.

“IL-8 (CXCL8), formerly known as neutrophil-activating peptide-1, is one of a group of chemokines, including CXCL1, 2, 3, 5, 6, and 8, that are neutrophil chemokines through a high-affinity receptor, CXCR2, and neutrophil activators through a low-affinity receptor, CXCR1.”

May combine two claims.

Keratinocytes produce large amounts of IL-1α and less IL-1β, whereas epidermal DCs, called Langerhans cells, as well as wound-infiltrating macrophages produce mostly IL-1β, but not IL-1α.

“Keratinocytes produce large amounts of IL-1α and less IL-1β,30,52 whereas epidermal DCs, called Langerhans cells, as well as wound-infiltrating macrophages produce mostly IL-1β, but not IL-1α.”

• cites [30] MacLeod AS, Rudolph R, Corriden R, Ye I, Garijo O, Havran WL Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair. J Immunol 2014; 192: 5695– 5702 24808367 PMC4048764 sourceNot checked yet

  Not checked in the free run.

• cites [52] Lee P, Lee DJ, Chan C, Chen SW, Ch'en I, Jamora C Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 2009; 458: 519– 523 19204729 PMC2666261 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Currently, there are 11 members of the IL-1 family, of which IL-1α and IL-1β are best characterized.

“Currently, there are 11 members of the IL-1 family, of which IL-1α and IL-1β are best characterized.”

May combine two claims.

Using a noninflammatory ex vivo wound healing model comprising organ-cultured human skin, hCAP18 is strongly expressed in healing skin epithelium and treatment with affinity-purified antibodies raised against LL-37 inhibits reepithelialization in a concentration-dependent manner.

“Using a noninflammatory ex vivo wound healing model comprising organ-cultured human skin, it has been shown that hCAP18 is strongly expressed in healing skin epithelium and that treatment with affinity-purified antibodies raised against LL-37 inhibits reepithelialization in a concentration-dependent manner.29”

• cites [29] Heilborn JD, Nilsson MF, Kratz G, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol 2003; 120: 379– 389 12603850 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

These chemokines are characterized by the sequence ELR at their N-terminus.

“These chemokines are characterized by the sequence ELR at their N-terminus.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Human β-defensins are a well-characterized group of AMPs that are abundantly expressed by multiple cell types such as keratinocytes and peripheral blood mononuclear cells.

“Human β-defensins are a well-characterized group of AMPs that are abundantly expressed by multiple cell types such as keratinocytes and peripheral blood mononuclear cells (PBMCs).”

May combine two claims.

MMP9 represents a double-edged element important in the early stage of wound healing, but destructive if it is not switched off at later stages.

“MMP9 thus represents a double-edged element important in the early stage of wound healing, but destructive if it is not switched off at later stages.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In man, one cathelicidin gene, named human cathelicidin antimicrobial peptide (CAMP), has been identified that encodes the 18 kD pre-pro-protein, hCAP18, which includes the C-terminal human antimicrobial peptide, LL-37.

“In man, one cathelicidin gene, named human cathelicidin antimicrobial peptide (CAMP), has been identified that encodes the 18 kD pre-pro-protein, hCAP18, which includes the C-terminal human antimicrobial peptide, LL-37.”

May combine two claims.

hCAP18 is detected in the inflammatory infiltrate and in the epithelium migrating over the wound bed.

“hCAP18 is detected in the inflammatory infiltrate and in the epithelium migrating over the wound bed.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The secretion pathways and mechanisms of IL-1α and IL-1β remain a matter of debate.

“However, the secretion pathways and mechanisms of IL-1α and IL-1β remain a matter of debate.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The NALP3 inflammasome comprises a multiprotein complex, which is required for activation of inflammatory caspases such as caspase-1.

“The NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome, comprises a multiprotein complex, which is required for activation of inflammatory caspases such as caspase-1.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

While IL-1α is translated into a biologically active form, IL-1β is translated as a propeptide that requires processing by caspase-1 in the inflammasome.

“While IL-1α is translated into a biologically active form, IL-1β is translated as a propeptide that requires processing by caspase-1 in the inflammasome.”

May combine two claims.

Although expressed in only very low levels in epidermal keratinocytes under resting conditions, cathelicidin is found in high levels in neutrophils, monocytes, natural killer cells, and T cells.

“Although expressed in only very low levels in epidermal keratinocytes under resting conditions, it is found in high levels in neutrophils, monocytes, natural killer (NK) cells, and T cells.40,41”

• cites [40] Agerberth B, Charo J, Werr J, et al. The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 2000; 96: 3086– 3093 11049988 sourceNot checked yet

  Not checked in the free run.

• cites [41] Buchau AS, Morizane S, Trowbridge J, et al. The host defense peptide cathelicidin is required for NK cell-mediated suppression of tumor growth. J Immunol 2010; 184: 369– 378 19949065 PMC2908520 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

AMPs can amplify the proinflammatory cytokine response and can thus, in some circumstances, assume pathogenic roles as in psoriasis, rosacea, and other skin diseases.

“AMPs can amplify the proinflammatory cytokine response and can thus, in some circumstances, assume pathogenic roles as in psoriasis, rosacea, and other skin diseases.36–38”

• cites [36] Buchau AS, Gallo RL Innate immunity and antimicrobial defense systems in psoriasis. Clin Dermatol 2007; 25: 616– 624 18021900 PMC2699547 sourceNot checked yet

  Not checked in the free run.

• cites [37] Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347: 1151– 1160 12374875 sourceNot checked yet

  Not checked in the free run.

• cites [38] Sorensen OE, Thapa DR, Roupe KM, et al. Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor. J Clin Invest 2006; 116: 1878– 1885 16778986 PMC1479426 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

This complex comprises the adaptor protein ASC and procaspase-1, both of which are expressed under homeostatic conditions in keratinocytes, and NALP3 whose expression is induced upon wounding.

“This complex comprises the adaptor protein (ASC) and procaspase-1, both of which are expressed under homeostatic conditions in keratinocytes, and NALP3 whose expression is induced upon wounding.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

IL-1α and IL-1β both bind to the IL-1 type I receptor to elicit an active immune response, whereas binding to IL-1R type II blocks IL-1 activity because it acts as a decoy receptor.

“IL-1α and Il-1β both bind to the IL-1 type I receptor to elicit an active immune response, whereas binding to IL-1R type II blocks IL-1 activity because it acts as a decoy receptor.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Keratinocytes, endothelial cells, fibroblasts, DCs, neutrophils, monocytes, macrophages, and innate lymphocytes such as NK cells, γδ T cells, as well as skin-resident T cells play major roles in the immune response of wound healing.

“Keratinocytes, endothelial cells, fibroblasts, DCs, neutrophils, monocytes, macrophages, and innate lymphocytes such as NK cells, γδ T cells, as well as skin-resident T cells play major roles in the immune response of wound healing.”

May combine two claims.

Nonhealing wounds are characterized by a dysregulation of the late inflammatory stage as nonhealing wounds rarely enter the proliferative phase of wound healing.

“What we do know is that nonhealing wounds are characterized by a dysregulation of the late inflammatory stage as nonhealing wounds rarely enter the proliferative phase of wound healing.”

May combine two claims.

There are contradictory reports on the effects of locally applied TNFα on granulation tissue formation in skin wound healing, indicating there is no consensus on the effects of local TNFα application.

“There are contradictory reports on the effects of locally applied TNFα on granulation tissue formation in skin wound healing,59,64,65 indicating there is no consensus on the effects of local TNFα application.”

• cites [59] Rapala K, Laato M, Niinikoski J, et al. Tumor necrosis factor alpha inhibits wound healing in the rat. Eur Surg Res 1991; 23: 261– 268 1802728 sourceNot checked yet

  Not checked in the free run.

• cites [64] Mooney DP, O'Reilly M, Gamelli RL Tumor necrosis factor and wound healing. Ann Surg 1990; 211: 124– 129 2301991 PMC1357954 sourceNot checked yet

  Not checked in the free run.

• cites [65] Salomon GD, Kasid A, Cromack DT, et al. The local effects of cachectin/tumor necrosis factor on wound healing. Ann Surg 1991; 214: 175– 180 1714269 PMC1358517 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Caspase-8 becomes downregulated upon wounding in the granular epidermal layer, and IL-1α subsequently mediates keratinocyte proliferation in a paracrine manner by first stimulating fibroblasts of the underlying dermis to secrete cytokines, which then induce keratinocyte division.

“Caspase-8 becomes downregulated upon wounding in the granular epidermal layer, and IL-1α subsequently mediates keratinocyte proliferation in a paracrine manner by first stimulating fibroblasts of the underlying dermis to secrete cytokines, which then induce keratinocyte division.”

• cites [52] Lee P, Lee DJ, Chan C, Chen SW, Ch'en I, Jamora C Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 2009; 458: 519– 523 19204729 PMC2666261 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Subsets of Th22 cells are resident in human skin, act as sentinel cells, and promote keratinocyte migration.

“Subsets of Th22 cells are resident in human skin, where they act as sentinel cells and promote keratinocyte migration.72”

• cites [72] Eyerich S, Eyerich K, Pennino D, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 2009; 119: 3573– 3555 19920355 PMC2786807Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

STAT3 is one of the key components for IL-6 receptor signaling whereby IL-6 can stimulate keratinocyte proliferation.

“Furthermore, STAT3 is one of the key components for IL-6 receptor signaling whereby IL-6 can stimulate keratinocyte proliferation.”

May combine two claims.

IL-17 is produced by Th17 cells, CD8+ T cells, and innate lymphocytes such as γδ T cells, NK cells, and NKT cells.

“IL-17 is not only the master cytokine of Th17 cells but is also produced by CD8+ T cells and innate lymphocytes, such as γδ T cells, NK cells, and NKT cells.73”

• cites [73] Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006; 24: 677– 688 16782025 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

High levels of TNFα are present in the wound fluid of chronic nonhealing wounds, leading to excessive inflammation ultimately resulting in impaired wound healing and tissue destruction.

“High levels of TNFα are present in the wound fluid of chronic nonhealing wounds, leading to excessive inflammation ultimately resulting in impaired wound healing and tissue destruction.63”

• cites [63] Cowin AJ, Hatzirodos N, Rigden J, Fitridge R, Belford DA Etanercept decreases tumor necrosis factor-alpha activity in chronic wound fluid. Wound Repair Regen 2006; 14: 421– 426 16939569 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

IL-6 enhances AMPs through direct signaling and through IL-17 as IL-6 mediates expansion of Th17 lymphocytes.

“IL-6 enhances AMPs through direct signaling and through IL-17 as IL-6 mediates expansion of Th17 lymphocytes.”

May combine two claims.

Elevation of TNFα leads to decreased production of granulation tissue, whereas low doses of TNFα promote collagen disposition.

“Elevation of TNFα leads to decreased production of granulation tissue, whereas low doses of TNFα promote collagen disposition,58–61 demonstrating the importance of accurate cytokine regulation during wound healing.”

• cites [58] Gill SE, Parks WC Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol 2008; 40: 1334– 1347 18083622 PMC2746915 sourceNot checked yet

  Not checked in the free run.

• cites [59] Rapala K, Laato M, Niinikoski J, et al. Tumor necrosis factor alpha inhibits wound healing in the rat. Eur Surg Res 1991; 23: 261– 268 1802728 sourceNot checked yet

  Not checked in the free run.

• cites [60] Steenfos HH Growth factors and wound healing. Scand J Plast Reconstr Surg Hand Surg 1994; 28: 95– 105 8079129 sourceNot checked yet

  Not checked in the free run.

• cites [61] Weinstein DA, Kirsner RS Refractory ulcers: the role of tumor necrosis factor-alpha. J Am Acad Dermatol 2010; 63: 146– 154 20542177 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The IL-6 receptor is a protein complex consisting of an IL-6 receptor subunit (IL-6R) and IL-6 signal transducer glycoprotein 130 (gp130).

“The IL-6 receptor is a protein complex consisting of an IL-6 receptor subunit (IL-6R) and IL-6 signal transducer glycoprotein 130 (gp130).”

May combine two claims.

In IL-1ra−/− mice, neutrophil recruitment is exaggerated and accompanied by augmented expression of IL-1s, TNFα, and CXC chemokines, MIP-2, and KC together with a failure to induce TGFβ1 and angiogenesis.

“Conversely, neutrophil recruitment is exaggerated and accompanied by augmented expression of IL-1s, TNFα, and CXC chemokines, macrophage inflammatory protein 2-alpha (MIP-2), and KC together with a failure to induce tumor growth factor β1 (TGFβ1) and angiogenesis.57”

• cites [57] Ishida Y, Gao JL, Murphy PM Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function. J Immunol 2008; 180: 569– 573 18097059 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

TNF-Rp55 mediates various activities of TNFα, including cytotoxicity, fibroblast proliferation, and induction of superoxide dismutase, whereas TNF-Rp75 mediates thymocyte and cytotoxic T cell proliferation.

“TNF-Rp55 mediates various activities of TNFα, including cytotoxicity, fibroblast proliferation, and induction of superoxide dismutase, whereas TNF-Rp75 mediates thymocyte and cytotoxic T cell proliferation.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

TNF-Rp55 is expressed ubiquitously in many cell types, whereas TNF-Rp75 expression is predominantly restricted to hematopoietic and endothelial cells.

“TNF-Rp55 is expressed ubiquitously in many cell types, whereas TNF-Rp75 expression is predominantly restricted to hematopoietic and endothelial cells.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

There are two types of receptors for TNFα signaling: one TNF receptor with a molecular mass of 55 kDa (TNF-Rp55) and one with a molecular mass of 75 kDa (TNF-Rp75).

“There are two types of receptors for TNFα signaling: one TNF receptor with a molecular mass of 55 kDa (TNF-Rp55) and one with a molecular mass of 75 kDa (TNF-Rp75).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

IL-6 induces the production of C-reactive protein, which can induce an inflammatory M1 phenotype in macrophages.

“IL-6 induces the production of C-reactive protein, which can induce an inflammatory M1 phenotype in macrophages.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

TNFα is a pleiotropic cytokine produced by a variety of cell types, including keratinocytes, macrophages, mast cells, and T cells.

“TNFα is a pleiotropic cytokine produced by a variety of cell types, including keratinocytes, macrophages, mast cells, and T cells.”

May combine two claims.

Recombinant IL-17A restores defective wound healing and AMP expression in IL-17A−/− skin.

“recombinant IL-17A restores defective wound healing and AMP expression in IL-17A−/− skin25;”

• cites [25] MacLeod AS, Hemmers S, Garijo O, et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J Clin Invest 2013; 123: 4364– 4374 24051381 PMC3784546 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Skin wounds in IL-1R−/− animals have decreased inflammation, decreased collagen levels, and improved restoration of normal skin architecture compared with skin wounds in wild-type mice.

“Skin wounds in IL-1R−/− animals have decreased inflammation, decreased collagen levels, and improved restoration of normal skin architecture compared with skin wounds in wild-type mice.55”

• cites [55] Thomay AA, Daley JM, Sabo E, et al. Disruption of interleukin-1 signaling improves the quality of wound healing. Am J Pathol 2009; 174: 2129– 2136 19389930 PMC2684178 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Various types of cells, including macrophages, T cells, fibroblasts, keratinocytes, and endothelial cells, produce IL-6, which exhibits various activities on a wide variety of cells, including lymphocytes, DCs, and keratinocytes.

“Various types of cells, including macrophages, T cells, fibroblasts, keratinocytes, and endothelial cells, produce IL-6, which exhibits various activities on a wide variety of cells, including lymphocytes, DCs, and keratinocytes.”

May combine two claims.

IL-1α levels are low in wound fluids from acute wounds, but are elevated in fluids from chronic wounds.

“IL-1α levels are low in wound fluids from acute wounds, but are elevated in fluids from chronic wounds.”

Probably not a substantial claim: may not pass S3 (load-bearing).

IL-17A signaling is mediated through IL-17 receptor A (IL-17RA) and IL-17RC.

“IL-17A signaling is mediated through IL-17 receptor A (IL-17RA) and IL-17RC,74,75”

• cites [74] Ely LK, Fischer S, Garcia KC Structural basis of receptor sharing by interleukin 17 cytokines. Nat Immunol 2009; 10: 1245– 1251 19838198 PMC2783927 sourceNot checked yet

  Not checked in the free run.

• cites [75] Toy D, Kugler D, Wolfson M, et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol 2006; 177: 36– 39 16785495 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Granulation tissue formation is a prerequisite for complete wound closure and healing.

“Granulation tissue formation is a prerequisite for complete wound closure and healing.”

May combine two claims.

IL-17A is required for the normal wound healing response, as IL-17A−/− mice show delayed closure of incisional wounds compared with wild-type controls.

“The requirement for IL-17A for the normal wound healing response has been demonstrated in a mouse model, where IL-17A−/− mice showed delayed closure of incisional wounds compared with wild-type controls.25”

• cites [25] MacLeod AS, Hemmers S, Garijo O, et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J Clin Invest 2013; 123: 4364– 4374 24051381 PMC3784546 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

IL-17A participates functionally in the healing response by augmenting the skin antimicrobial barrier and by regulating epidermal regeneration and differentiation.

“IL-17A participates functionally in the healing response by augmenting the skin antimicrobial barrier and by regulating epidermal regeneration and differentiation.25,28”

• cites [25] MacLeod AS, Hemmers S, Garijo O, et al. Dendritic epidermal T cells regulate skin antimicrobial barrier function. J Clin Invest 2013; 123: 4364– 4374 24051381 PMC3784546 sourceNot checked yet

  Not checked in the free run.

• cites [28] Lai Y, Li D, Li C, et al. The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. Immunity 2012; 37: 74– 84 22727489 PMC3828049 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

IL-1β together with IL-23 and IL-6 is important for Th17 differentiation, and IL-17 regulates antimicrobial barrier function.

“IL-1β together with IL-23 and IL-6 is important for Th17 differentiation, and IL-17 regulates antimicrobial barrier function as discussed below.”

May combine two claims.

Wound healing studies in TNF-Rp55−/− mice showed enhanced collagen accumulation with reduced leukocyte infiltration at wound sites.

“Wound healing studies in TNF-Rp55−/− mice showed in enhanced collagen accumulation with reduced leukocyte infiltration at wound sites.66”

• cites [66] Mori R, Kondo T, Ohshima T, Ishida Y, Mukaida N Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration. FASEB J 2002; 16: 963– 974 12087057 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

IL-22 has an essential role in the wound healing response, demonstrated in IL-22−/− mice.

“An essential role for IL-22 in the wound healing response has been demonstrated in IL-22−/− mice.”

• cites [87] McGee HM, Schmidt BA, Booth CJ, et al. IL-22 promotes fibroblast-mediated wound repair in the skin. J Invest Dermatol 2013; 133: 1321– 1329 23223145 PMC3610794 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Reduction in PTEN extends the activation of AKT, which turns off the inflammatory state and promotes the anti-inflammatory state.

“The reduction in PTEN extends the activation of protein kinase B (AKT), which turns off the inflammatory state and promotes the anti-inflammatory state.”

• cites [99] Perdiguero E, Kharraz Y, Serrano AL, Munoz-Canoves P MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair. Cell Cycle 2012; 11: 877– 886 22361726 sourceNot checked yet

  Not checked in the free run.

• cites [100] Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, et al. p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair. J Cell Biol 2011; 195: 307– 322 21987635 PMC3198158 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Overexpression of miR-146 in human psoriatic skin has been suggested to reflect insufficient compensation of overt skin inflammation.

“Its overexpression in human psoriatic skin has been suggested to reflect insufficient compensation of overt skin inflammation.91”

• cites [91] Sonkoly E, Wei T, Janson PC, et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS One 2007; 2: e610 17622355 PMC1905940 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Fibroblasts and keratinocytes show a response to the elevation of miR-21 that differs from macrophages and stimulates migration.

“Fibroblasts and keratinocytes show a response to the elevation of miR-21 that differs from macrophages and stimulates migration.102”

• cites [102] Yang X, Wang J, Guo SL, et al. miR-21 promotes keratinocyte migration and re-epithelialization during wound healing. Int J Biol Sci 2011; 7: 685– 690 21647251 PMC3107477 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

IL-22 mediates its functions by binding to its heterodimeric receptor consisting of IL-10 receptor β2 (IL-10Rβ2) and IL-22 receptor (IL-22R) and activating signaling pathways that stimulate STAT3 phosphorylation and nuclear translocation.

“IL-22 mediates its functions by binding to its heterodimeric receptor consisting of IL-10 receptor β2 (IL-10Rβ2) and IL-22 receptor (IL-22R) and activating signaling pathways, which stimulate STAT3 phosphorylation and nuclear translocation.80–84”

• cites [80] Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 2001; 167: 3545– 3549 11564763 sourceNot checked yet

  Not checked in the free run.

• cites [81] Dumoutier L, Lejeune D, Hor S, Fickenscher H, Renauld JC Cloning of a new type II cytokine receptor activating signal transducer and activator of transcription (STAT)1, STAT2 and STAT3. Biochem J 2003; 370: 391– 396 12521379 PMC1223207 sourceNot checked yet

  Not checked in the free run.

• cites [82] Kotenko SV, Izotova LS, Mirochnitchenko OV, et al. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J Immunol 2001; 166: 7096– 7103 11390454 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

miR-21 is increased in the skin of db/db mice but reduced in diabetic wound healing.

“miR-21 has been reported to be increased in the skin of db/db mice, but reduced in diabetic wound healing.103”

• cites [103] Madhyastha R, Madhyastha H, Nakajima Y, Omura S, Maruyama M MicroRNA signature in diabetic wound healing: promotive role of miR-21 in fibroblast migration. Int Wound J 2012; 9: 355– 361 22067035 PMC7950390 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

miR-21 appears to be involved in both the termination of the inflammatory phase of wound healing and the start of the proliferative repair phase.

“Thus, miR-21 appears to be involved in both the termination of the inflammatory phase of wound healing and the start of the proliferative repair phase.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

miR-203 is increased in psoriasis and its targets include p63, suppressor of cytokine signaling 3 (SOCS3), and IL-8.

“miR-203 is also increased in psoriasis and its targets include p63, suppressor of cytokine signaling 3 (SOCS3), and IL-8,89”

• cites [89] Sonkoly E, Stahle M, Pivarcsi A MicroRNAs: novel regulators in skin inflammation. Clin Exp Dermatol 2008; 33: 312– 315 18419608 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Multiple pathways induce M2 and M2-like macrophages, including IL-4/IL-13-dependent signaling, TLR and IL-1R signaling with adenosine A(2A)R, CCL18, and CX3CL1.

“Recent studies suggest multiple pathways by which macrophages are induced to develop into M2 and M2-like macrophages. One pathway occurs through an IL-4/IL-13–dependent signaling cascade,95 a second is mediated through TLR and IL-1R signaling and adenosine-sensing receptor A(2A)R,56,95,96 a third is mediated by CCL18,97 and a fourth involves CX3CL1 (fractalkine).57”

• cites [95] Ferrante CJ, Pinhal-Enfield G, Elson G, et al. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Ralpha) signaling. Inflammation 2013; 36: 921– 931 23504259 PMC3710311 sourceNot checked yet

  Not checked in the free run.

• cites [96] Pinhal-Enfield G, Ramanathan M, Hasko G, et al. An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A(2A) receptors. Am J Pathol 2003; 163: 711– 721 12875990 PMC1868201 sourceNot checked yet

  Not checked in the free run.

• cites [97] Schraufstatter IU, Zhao M, Khaldoyanidi SK, Discipio RG The chemokine CCL18 causes maturation of cultured monocytes to macrophages in the M2 spectrum. Immunology 2012; 135: 287– 298 22117697 PMC3372745 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

p38 induces miR-21, one of whose targets is PTEN.

“It also induces miR-21, one of whose targets is phosphatase with a tensin motif (PTEN).”

• cites [99] Perdiguero E, Kharraz Y, Serrano AL, Munoz-Canoves P MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair. Cell Cycle 2012; 11: 877– 886 22361726 sourceNot checked yet

  Not checked in the free run.

• cites [100] Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, et al. p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair. J Cell Biol 2011; 195: 307– 322 21987635 PMC3198158 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

miR-146 targets SMAD4 and thus may inhibit the TGFβ induction of the M2 phenotype.

“Furthermore, miR-146 targets sma and mothers against decapentaplegic-related protein 4 (SMAD4) and thus may inhibit the TGFβ induction of the M2 phenotype.92”

• cites [92] Bostjancic E, Glavac D Importance of microRNAs in skin morphogenesis and diseases. Acta Dermatovenerol Alp Pannonica Adriati 2008; 17: 95– 102 18853072Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Under normal conditions, this process appears to possess an intrinsic time course.

“Under normal conditions, this process appears to possess an intrinsic time course.”

May combine two claims.

miR-146 suppresses the production of inflammatory mediators under homeostatic conditions, serves as a negative feedback regulator following TLR2 activation, and represses neutrophil chemotaxis.

“miR-146 suppresses the production of inflammatory mediators under homeostatic conditions, serves as a negative feedback regulator following TLR2 activation, and represses neutrophil chemotaxis.90”

• cites [90] Meisgen F, Xu Landen N, Wang A, et al. MiR-146a negatively regulates TLR2-induced inflammatory responses in keratinocytes. J Invest Dermatol 2014; 134: 1931– 1940 24670381 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CX3CR1−/− mice show delayed wound healing that can be restored by bone marrow transplants from wild-type mice, implying that the relevant site of the receptor is a bone marrow-derived cell such as the macrophage.

“and that CX3CR1−/− mice show delayed wound healing that could be restored by bone marrow transplants from wild-type mice, implying that the relevant site of the receptor is a bone marrow-derived cell, such as the macrophage.”

• cites [57] Ishida Y, Gao JL, Murphy PM Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function. J Immunol 2008; 180: 569– 573 18097059 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

It is possible that venous ulcers and diabetic ulcers each show a derangement of the macrophage phenotypic switch, but in different ways, in each case important to an inappropriate immune response.

“Thus, it is possible that venous ulcers and diabetic ulcers each show a derangement of the macrophage phenotypic switch, but in different ways, in each case important to an inappropriate immune response.”

Probably not a substantial claim: may not pass S4 (based).

Recruited neutrophils and macrophages secrete cytokines that stimulate further recruitment of immune cells.

“Recruited neutrophils and macrophages secrete cytokines that stimulate further recruitment of immune cells.”

May combine two claims.

In fibroblasts and keratinocytes, p38 induces granulation tissue and migration.

“In fibroblasts and keratinocytes, it induces granulation tissue and migration.”

May combine two claims.

In db/db mice, inhibition of p38 improves wound healing, perhaps by reducing the inflammatory phase and delaying anti-inflammatory macrophage conversion to allow wound clearance to be completed.

“In db/db mice, inhibition of p38 has been reported to improve wound healing, perhaps by reducing the inflammatory phase and delaying anti-inflammatory macrophage conversion to allow wound clearance to be completed, thus allowing healing.104”

• cites [104] Medicherla S, Wadsworth S, Cullen B, et al. p38 MAPK inhibition reduces diabetes-induced impairment of wound healing. Diabetes Metab Syndr Obes 2009; 2: 91– 200 21437122 PMC3048002 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Interference with this mechanism leads to delayed wound healing and the system shows abnormalities in chronic wounds.

“Interference with this mechanism leads to delayed wound healing and the system shows abnormalities in chronic wounds.”

May combine two claims.

The inflammatory phase is limited in duration in normal wound healing and is succeeded by a prorepair phase; a central player in this switch is a phenotypic change in the macrophage.

“The inflammatory phase is limited in its duration in normal wound healing and is succeeded by a prorepair phase. A central player in this switch is a phenotypic change in the macrophage.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Similar mechanisms have long been suggested for human patients.

“Similar mechanisms have long been suggested for human patients.110”

• cites [110] Sindrilaru A, Scharffetter-Kochanek K Disclosure of the culprits: macrophages-versatile regulators of wound healing. Adv Wound Care (New Rochelle) 2013; 2: 357– 368 24587973 PMC3842885 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

The innate immune system comprises a network of interacting mechanisms that provide a rapid response to clear microbial contamination upon skin injury.

“The innate immune system comprises a network of interacting mechanisms that provide a rapid response to clear microbial contamination upon skin injury.”

May combine two claims.

Active p38 controls the secretion of inflammatory cytokines and induces miR-21 that indirectly activates AKT and induces the anti-inflammatory macrophage phenotype.

“Active p38 not only controls the secretion of inflammatory cytokines but also induces miR-21 that indirectly activates AKT and induces the anti-inflammatory macrophage phenotype.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

First-line defense molecules include antimicrobial peptides, CXC chemokines secreted by fibroblasts and keratinocytes, IL-1, and TNFα.

“First-line defense molecules include antimicrobial peptides, CXC chemokines secreted by fibroblasts and keratinocytes, IL-1, and TNFα.”

May combine two claims.

Failure of this switch is a candidate for the process that leads to chronic wounds; factors involved in control of this step through p38 include IL-4/IL-13, TLR and adenosine, and fractalkine.

“Failure of this switch is a candidate for the process that leads to chronic wounds. Factors involved in the control of this step through p38 include IL-4/IL-13, TLR and adenosine, and fractalkine.”

May combine two claims.

This step is controlled by IL-4/IL-13, TLR activation, adenosine, and fractalkine and is influenced by IL-1 and involves a signal transduction pathway whose function depends on a calibrated activity of the stress-associated MAPK, p38.

“This step is controlled by IL-4/IL-13, TLR activation, adenosine, and fractalkine and is influenced by IL-1 and involves a signal transduction pathway whose function depends on a calibrated activity of the stress-associated MAPK, p38.”