Macrophage polarization: An opportunity for improved outcomes in biomaterials and regenerative medicine

In the paper

“Macrophages assume diverse and context dependent phenotypes, which are defined by their functional properties and patterns of gene expression.”

In the paper

“These studies indicate that macrophages possess remarkable functional plasticity and, therefore, can play both positive and negative roles in the pathogenesis of disease and tissue remodeling.”

In the paper

“Broadly, polarized macrophages are referred to as having either an M1 or an M2 phenotype, mimicking the Th1/Th2 nomenclature which has been described for T helper cells [10].”

What the sources say

• Not checked yetcites [10] Mills, 2000, M-1/M-2 macrophages and the Th1/Th2 paradigm, J Immunol source

In the paper

“In general, M1 activated macrophages express interleukin (IL)-12high, IL-23high, IL-10low; metabolize arginine, produce high levels of inducible nitric oxide synthase (iNOS); secrete toxic reactive oxygen and nitric oxygen intermediates and inflammatory cytokines such as IL-1β, IL-6, and TNFα; and are inducer and effector cells in Th1 type inflammatory responses.”

In the paper

“While the term ‘M2’ encompasses all non-classically activated macrophages, M2 macrophages have been shown to include three well recognized sub-populations (M2a, M2b, and M2c), each with its own distinct inducers, markers, and functions.”

What the sources say

• Not checked yetcites [8] Mantovani, 2004, The chemokine system in diverse forms of macrophage activation and polarization, Trends Immunol source
• Not checked yetcites [12] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat Rev Immunol source
• Not checked yetcites [13] Gordon, 2003, Alternative activation of macrophages, Nat Rev Immunol source

In the paper

“It has been shown that unlike lymphocytes, where cellular phenotype is relatively fixed upon differentiation, macrophages have dynamic and plastic phenotypes that change with local microenvironmental signals [5,14–16].”

What the sources say

• Not checked yetcites [5] Sunderkotter, 2004, Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response, J Immunol source
• Not checked yetcites [14] Stout, 2009, Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages, J Leukoc Biol source
• Not checked yetcites [15] Porcheray, 2005, Macrophage activation switching: an asset for the resolution of inflammation, Clin Exp Immunol source
• Not checked yetcites [16] Stout, 2005, Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences, J Immunol source

In the paper

“M2 activated macrophages express IL-12low, IL-23low, and IL-10high; have high levels of scavenger, mannose, and galactose receptors; produce arginase in the place of arginine, subsequently producing ornithine and polyamines; and are involved in polarized Th2 reactions.”

In the paper

“M1, or “classically activated” pro-inflammatory macrophages are induced by interferon (IFN)γ alone or in combination with lipopolysaccharide (LPS, endotoxin) or tumor necrosis factor (TNF)α.”

In the paper

“This profile leads to an inability to mount a tumor-destructive Th1 type response while also driving the recruitment and development of T-regulatory cells (T-regs) and leading to a more tumor-permissive environment.”

In the paper

“Interestingly, TAMs are found largely within hypoxic regions of tumors and have been shown drive the angiogenic response that is required for tumor survival and metastasis [40,41].”

What the sources say

• Not checked yetcites [40] Lin, 2006, Macrophages regulate the angiogenic switch in a mouse model of breast cancer, Cancer Res source
• Not checked yetcites [41] Lin, 2007, Tumor-associated macrophages press the angiogenic switch in breast cancer, Cancer Res source

In the paper

“These cells, termed “tumor associated macrophages” (TAM), are characterized by production of large amounts of IL-10, low production of inflammatory cytokines and reactive oxygen intermediates, and poor antigen presenting capabilities.”

What the sources say

• Not checked yetcites [36] Sica, 2008, Macrophage polarization in tumour progression, Semin Cancer Biol source
• Not checked yetcites [39] Porta, 2007, Tumor promotion by tumor-associated macrophages, Adv Exp Med Biol source

In the paper

“The chronic production of large quantities of inflammatory mediators in these cases can lead, through a number of pathways, to tumor cell proliferation and survival or to the induction of genetic instabilities in normal cells, with resultant expression of oncogenes and production of immune suppressive cytokines [37,38].”

What the sources say

• Not checked yetcites [37] Porta, 2011, Mechanisms linking pathogens-associated inflammation and cancer, Cancer Lett source
• Not checked yetcites [38] Mantovani, 2008, Cancer-related inflammation, Nature source

In the paper

“A number of recent studies have begun to assess the polarization profile of plaque infiltrating macrophages, suggesting that the initial infiltrating population in early atherosclerosis is heterogeneous, but possesses a predominantly M2-like phenotype [28,45].”

What the sources say

• Not checked yetcites [28] Bouhlel, 2007, PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties, Cell Metab source
• Not checked yetcites [45] Johnson, 2009, Macrophage heterogeneity in atherosclerotic plaques, Curr Opin Lipidol source

In the paper

“For example, in vitro experiments have shown that LPS stimulated, classically activated macrophages, become Toll-like receptor (TLR)-tolerant and unable to produce similarly elevated levels of pro-inflammatory cytokines upon second exposure to LPS [16–18].”

What the sources say

• Not checked yetcites [16] Stout, 2005, Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences, J Immunol source
• Not checked yetcites [17] Biswas, 2009, Endotoxin tolerance: new mechanisms, molecules and clinical significance, Trends Immunol source
• Not checked yetcites [18] Foster, 2007, Gene-specific control of inflammation by TLR-induced chromatin modifications, Nature source

In the paper

“Specifically, STAT1 and IRF5 have been shown to be involved in polarization and maintenance of an M1 phenotype while STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in polarization and maintenance of an M2 phenotype [23–30].”

What the sources say

• Not checked yetcites [23] Darnell, 1994, Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins, Science source
• Not checked yetcites [24] Ruffell, 2009, A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair, Proc Natl Acad Sci USA source
• Not checked yetcites [25] Satoh, 2010, The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection, Nat Immunol source
• Not checked yetcites [26] Takeda, 1996, Essential role of Stat6 in IL-4 signalling, Nature source
• Not checked yetcites [27] Ohmori, 1997, IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages, J Immunol source
• Not checked yetcites [28] Bouhlel, 2007, PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties, Cell Metab source
• Not checked yetcites [29] Odegaard, 2007, Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance, Nature source
• Not checked yetcites [30] Savitsky, 2010, Regulation of immunity and oncogenesis by the IRF transcription factor family, Cancer Immunol Immunother source

In the paper

“That is, macrophages can play both beneficial and detrimental roles in the process of tissue remodeling and, in many cases, an efficient and timely phenotypic switch is essential for appropriate and functional remodeling as opposed to a deleterious or scar tissue outcome with a loss of function.”

In the paper

“Overall, a complex multifactorial etiology of periodontal disease including the host immune response and environmental factors has been suggested likely involving multiple cell types [78].”

What the sources say

• Not checked yetcites [78] Cullinan, 2003, Acquisition and loss of Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans and Prevotella intermedia over a 5-year period: effect of a triclosan/copolymer dentifrice, J Clin Periodontol source

In the paper

“Foam cell macrophages exhibit a highly activated phenotype leading to production of pro-inflammatory mediators and MMPs that destabilize the plaques, potentially leading to thromboembolism [56].”

What the sources say

• Not checked yetcites [56] Newby, 2005, Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture, Physiol Rev source

In the paper

“Importantly, periodontal disease has been shown to have many mechanistic parallels and links to the pathogenic processes of atherosclerosis and obesity [69].”

What the sources say

• Not checked yetcites [69] Zelkha, 2010, Periodontal innate immune mechanisms relevant to atherosclerosis and obesity, Periodontol 2000 source

In the paper

“The default response to tissue injury has been described as occurring in four stages: hemostasis, inflammation, proliferation, and remodeling [86].”

What the sources say

• Not checked yetcites [86] Diegelmann, 2004, Wound healing: an overview of acute, fibrotic and delayed healing, Front Biosci source

In the paper

“These cells are of a predominantly pro-inflammatory phenotype and secrete cytokines and chemokines that promote the further recruitment of leukocytes to the site of injury [89,91].”

What the sources say

• Not checked yetcites [89] Barrientos, 2008, Growth factors and cytokines in wound healing, Wound Repair Regen source
• Not checked yetcites [91] Werner, 2003, Regulation of wound healing by growth factors and cytokines, Physiol Rev source

In the paper

“In each case, the pathogenesis of disease results from inappropriate macrophage polarization, an inhibition of macrophage polarization, or an inability to resolve a chronic polarization towards the M1 or M2 extreme.”

In the paper

“A number of studies have shown that TLR-4 deficient mice are not protected from diet-induced obesity, but are protected from obesity-induced insulin resistance [74,76,77].”

What the sources say

• Not checked yetcites [74] Shi, 2006, TLR4 links innate immunity and fatty acid-induced insulin resistance, J Clin Invest source
• Not checked yetcites [76] Tsukumo, 2007, Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance, Diabetes source
• Not checked yetcites [77] Saberi, 2009, Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice, Cell Metab source

In the paper

“In normal rodents and humans, ATMs make up as much as ten percent of the cellular constituents of the tissue [62]. In comparison, it has been shown that in obese subjects that number rises to as much as 40% [62].”

What the sources say

• Not checked yetcites [62] Weisberg, 2006, CCR2 modulates inflammatory and metabolic effects of high-fat feeding, J Clin Invest source

In the paper

“Additionally, damage associated molecular pattern molecules, such as heat shock proteins, released from dead or dying adipocytes may signal through TLR pathways, producing activation of the NLRP3 inflammasome and promotion of a pro-inflammatory phenotype [75].”

What the sources say

• Not checked yetcites [75] Vandanmagsar, 2011, The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance, Nat Med source

In the paper

“However, clodronate treatment was not shown to reduce the size of plaques that were already established prior to treatment, suggesting that such a treatment may be most effective in the early stages of disease progression [59].”

What the sources say

• Not checked yetcites [59] Stoneman, 2007, Monocyte/macrophage suppression in CD11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques, Circ Res source

In the paper

“These cells produce high levels of TNFα, IL-6, and IL-1β, all of which are also observed in increased levels of adipose tissue from insulin resistant individuals.”

What the sources say

• Not checked yetcites [63] Olefsky, 2010, Macrophages, inflammation, and insulin resistance, Annu Rev Physiol source
• Not checked yetcites [69] Zelkha, 2010, Periodontal innate immune mechanisms relevant to atherosclerosis and obesity, Periodontol 2000 source
• Not checked yetcites [70] Lumeng, 2007, Obesity induces a phenotypic switch in adipose tissue macrophage polarization, J Clin Invest source
• Not checked yetcites [71] Prieur, 2011, Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice, Diabetes source

In the paper

“Macrophages also remove apoptotic neutrophils, the phagocytosis of which may lead to a change toward a more reparative (M2) macrophage phenotype and the resolution of the inflammatory phase of wound healing [94–96].”

What the sources say

• Not checked yetcites [94] Erwig, 2007, Immunological consequences of apoptotic cell phagocytosis, Am J Pathol source
• Not checked yetcites [95] Fadok, 1998, Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells, Biochem Soc Trans source
• Not checked yetcites [96] Sylvia, 2003, The role of neutrophil apoptosis in influencing tissue repair, J Wound Care source

In the paper

“Studies in PPARγ deficient mice exhibit impaired M2 macrophage function and susceptibility to diet-induced inflammation and insulin resistance [29,65–67].”

What the sources say

• Not checked yetcites [29] Odegaard, 2007, Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance, Nature source
• Not checked yetcites [65] Pascual, 2007, Macrophage peroxisome proliferator activated receptor gamma as a therapeutic target to combat Type 2 diabetes, Expert Opin Ther Targets source
• Not checked yetcites [66] Hevener, 2007, Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones, J Clin Invest source
• Not checked yetcites [67] Norris, 2003, Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones, J Clin Invest source

In the paper

“These observations suggest that therapies which prevent the M2 to M1 switch or deplete M1 macrophages selectively may be of clinical utility for the stabilization of atherosclerotic plaques.”

In the paper

“These cells have been shown to possess a predominantly pro-inflammatory phenotype following injury, resulting in a microenvironment that is cytotoxic and propagates tissue damage and scar tissue deposition [128].”

What the sources say

• Not checked yetcites [128] Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, J Neurosci source

In the paper

“The results of the study showed that a predominantly M1 phenotype was induced immediately following injury and persisted within spinal cord lesions. A small number of M2 macrophages were also seen in the site of injury at early time points; however, these cells were not observed at later time points in the remodeling process, suggesting that the M1 to M2 phenotype shift does not occur in the same”

What the sources say

• Not checked yetcites [128] Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, J Neurosci source

In the paper

“It is interesting to note that diabetes and advanced age are also associated with delayed or impaired wound healing, and with a reduced ability to transition from an M1 to an M2 macrophage phenotype [63,108].”

What the sources say

• Not checked yetcites [63] Olefsky, 2010, Macrophages, inflammation, and insulin resistance, Annu Rev Physiol source
• Not checked yetcites [108] Mahbub, 2012, Advanced age impairs macrophage polarization, J Interferon Cytokine Res source

In the paper

“Studies have also suggested that macrophage polarization may play an important role in the process of muscle wasting which occurs in models of muscular dystrophy [124,126,127].”

• Also stated in: § 3.2. The role of macrophage polarization in tissue remodeling · plain

  “Unlike the normal process of muscle tissue remodeling, this environment is not characterized by a switch from M1 to M2. Rather, the mixed polarization state persists, constantly recruiting progenitor cells which then fail to differentiate along normal pathways resulting in ineffective remodeling and depletion of progenitor cell reserves within the tissue.”

What the sources say

• Not checked yetcites [124] Villalta, 2011, Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype, Hum Mol Genet source
• Not checked yetcites [126] Villalta, 2009, Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy, Hum Mol Genet source
• Not checked yetcites [127] Villalta, 2011, IFN-gamma promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation, J Immunol source

In the paper

“Of note, however, investigators identified two clusters of genes, associated with macrophage M1/ M2 polarization, which were upregulated transiently during the wound healing process.”

What the sources say

• Not checked yetcites [105] Deonarine, 2007, Gene expression profiling of cutaneous wound healing, J Transl Med source

In the paper

“Briefly, the events that occur during skeletal muscle repair are thought to fall into three well defined stages including (1) proliferation, (2) early differentiation, and (3) terminal differentiation [110].”

What the sources say

• Not checked yetcites [110] Le Grand, 2007, Skeletal muscle satellite cells and adult myogenesis, Curr Opin Cell Biol source

In the paper

“For example, IL-10 secreted by M2 macrophages is known both to drive a transition from an M1 to an M2 phenotype as well as to promote the fusion and maturation of myotubes [112,125].”

What the sources say

• Not checked yetcites [112] Arnold, 2007, Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis, J Exp Med source
• Not checked yetcites [125] Strle, 2007, Novel activity of an anti-inflammatory cytokine: IL-10 prevents TNFalpha-induced resistance to IGF-I in myoblasts, J Neuroimmunol source

In the paper

“These cytokines include EGF, b-FGF, TGF-α, TGF-β, VEGF, and others depending on the nature of the injured tissue [86].”

What the sources say

• Not checked yetcites [86] Diegelmann, 2004, Wound healing: an overview of acute, fibrotic and delayed healing, Front Biosci source

In the paper

“The mechanisms of this switch from an M1 to an M2 phenotype during dermal remodeling are not well described, but are thought to include phenotypic changes caused by the phagocytosis of apoptotic cells and debris by M1 macrophages [94–96].”

What the sources say

• Not checked yetcites [94] Erwig, 2007, Immunological consequences of apoptotic cell phagocytosis, Am J Pathol source
• Not checked yetcites [95] Fadok, 1998, Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells, Biochem Soc Trans source
• Not checked yetcites [96] Sylvia, 2003, The role of neutrophil apoptosis in influencing tissue repair, J Wound Care source

In the paper

“A number of studies have shown that reduction of the number of monocytes available to participate in the response following muscle injury via depletion of circulating cells results in slowed removal of cellular debris and delayed muscle tissue remodeling [112–114].”

What the sources say

• Not checked yetcites [112] Arnold, 2007, Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis, J Exp Med source
• Not checked yetcites [113] Summan, 2006, Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study, Am J Physiol Regul Integr Comp Physiol source
• Not checked yetcites [114] Tidball, 2007, Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo, J Physiol source

In the paper

“Following the initial pro-inflammatory phase, a switch to an M2 macrophage phenotype and resolution of the inflammatory response has been shown to occur with the initial stages of differentiation of muscle satellite cells into differentiated skeletal muscle cells [123].”

What the sources say

• Not checked yetcites [123] St Pierre, 1994, Differential response of macrophage subpopulations to soleus muscle reloading after rat hindlimb suspension, J Appl Physiol source

In the paper

“That is, when placed into culture, muscle progenitor cells proliferate, express early markers of differentiation along a muscle phenotype (MyoD, Myf5), and then fuse and form mature myotubes with a contractile phenotype in the absence of immune cells or their secreted products [110].”

What the sources say

• Not checked yetcites [110] Le Grand, 2007, Skeletal muscle satellite cells and adult myogenesis, Curr Opin Cell Biol source

In the paper

“In vivo, however, the response following muscle tissue injury has been shown to include a significant number of infiltrating inflammatory cells which can exceed 100,000 cells/mm3 of tissue [111].”

What the sources say

• Not checked yetcites [111] Wehling, 2001, A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice, J Cell Biol source

In the paper

“Following the deposition of significant amounts of ECM (predominantly collagens type I and III) during the proliferative phase, the remodeling phase of wound healing begins. This phase is characterized by MMP- and tissue inhibitor of metalloproteinase (TIMP)-mediated degradation and remodeling of the newly deposited collagen, generally resulting in scar tissue formation/maturation [86,100].”

What the sources say

• Not checked yetcites [86] Diegelmann, 2004, Wound healing: an overview of acute, fibrotic and delayed healing, Front Biosci source
• Not checked yetcites [100] Gill, 2008, Metalloproteinases and their inhibitors: regulators of wound healing, Int J Biochem Cell Biol source

In the paper

“The transition to an M2 environment not only serves to attenuate the inflammatory response and potentially cytotoxic production of nitric oxide, but also to drive the differentiation and fusion of cells [114,124].”

What the sources say

• Not checked yetcites [114] Tidball, 2007, Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo, J Physiol source
• Not checked yetcites [124] Villalta, 2011, Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype, Hum Mol Genet source

In the paper

“In this study it was shown that the deletion of two of the binding sites in the CREB-C/EBPβ pathway blocked the induction of M2 associated genes (Msr1, IL-10, IL-13ra, and Arg-1), while M1 gene (IL-1, IL-6, IL-12b, TNFα) expression was not affected.”

• Also stated in: § 3.2. The role of macrophage polarization in tissue remodeling · plain

  “However, the tissue that formed within the site of remodeling was highly fibrotic and associated with a decrease in myofiber size. This result was in direct contrast to wild-type mice that exhibited full recovery of the injured muscle.”

What the sources say

• Not checked yetcites [24] Ruffell, 2009, A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair, Proc Natl Acad Sci USA source

In the paper

“However, it has also been shown that proinflammatory cytokines may inhibit muscle progenitor cell differentiation and that the reactive oxygen species that are produced by M1 cells (nitric oxide) can be cytotoxic if present in sufficient quantities, demonstrating the need for resolution of the proinflammatory response for muscle recovery to proceed beyond this initial stage [120–122].”

What the sources say

• Not checked yetcites [120] Nguyen, 2003, Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro, J Physiol source
• Not checked yetcites [121] Szalay, 1997, TNF inhibits myogenesis and downregulates the expression of myogenic regulatory factors myoD and myogenin, Eur J Cell Biol
• Not checked yetcites [122] Tsujinaka, 1996, Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice, J Clin Invest source

In the paper

“This phenotypic transition impairment suggests a potential, but as yet unexplored, link between defective macrophage polarization switching or disposition towards a pro-inflammatory phenotype and impaired tissue remodeling.”

In the paper

“This bimodal outcome scenario suggests that the default response following CNS injury is a chronic pro-inflammatory, M1 type response which leads to decreased viability of the neurons within the site of injury, and that induction of a more M2 type response may be capable of promoting a more constructive tissue remodeling type environment.”

In the paper

“The byproducts of wear include particulate polymeric, ceramic and metallic debris (mostly in the nano, submicron, and micron size range) and in the case of metal-on-metal implants, metallic ions [143]. These byproducts are well known to cause pro-inflammatory responses which can persist for the life of the implant [144,145].”

What the sources say

• Not checked yetcites [143] Shanbhag, 1994, Composition and morphology of wear debris in failed uncemented total hip replacement, J Bone Jt Surg Br source
• Not checked yetcites [144] Goodman, 2007, Wear particles, periprosthetic osteolysis and the immune system, Biomaterials source
• Not checked yetcites [145] Ingham, 2005, The role of macrophages in osteolysis of total joint replacement, Biomaterials source

In the paper

“Neurons which were exposed to media conditioned by M1 macrophages were shown to exhibit a decrease in viability as well as a decrease in neurite length, while those cells exposed to media conditioned by M2 macrophages showed improved survival and a greater degree of neurite extension.”

What the sources say

• Not checked yetcites [128] Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, J Neurosci source

In the paper

“Briefly, macrophages regulate the process of fibrosis through the production of cytokines which directly activate fibroblasts (TGF-β, PDGF, insulin like growth factor (IGF)-1), the production of MMPs and TIMPs which drive ECM remodeling, and M1 factors which drive a “feed-forward” state of inflammation and remodeling (IL-1b) [102].”

What the sources say

• Not checked yetcites [102] Wynn, 2008, Cellular and molecular mechanisms of fibrosis, J Pathol source

In the paper

“It was noted that those materials possessing pores of 30–40 mm healed with minimal fibrosis and the highest vascularity [149]. These pores were also found to be heavily infiltrated by macrophages, but not foreign body giant cells.”

What the sources say

• Not checked yetcites [149] Fukano, 2010, Epidermal and dermal integration into sphere-templated porous poly(2-hydroxyethyl methacrylate) implants in mice, J Biomed Mater Res A source

In the paper

“In the case of TJR, these processes result in periprosthetic bone resorption (osteolysis) which undermines the bony foundation of the implant and can lead to chronic synovitis, loosening and pathologic fracture [144].”

What the sources say

• Not checked yetcites [144] Goodman, 2007, Wear particles, periprosthetic osteolysis and the immune system, Biomaterials source

In the paper

“It was also shown that the optimal time for injection of these cells was one week post-injury, suggesting that early M1 polarization may play a beneficial role in CNS remodeling following injury, similar to that observed in skeletal muscle [136].”

What the sources say

• Not checked yetcites [136] Ziv, 2006, Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury, Proc Natl Acad Sci USA source

In the paper

“While the specific mode of failure is highly context dependent, a major complication following the implantation of any material is the development of a foreign body reaction (FBR).”

• Also stated in: § 4.1. The role of macrophage polarization following the implantation of long-term medical devices · boosted

  “The FBR consists of a set of well known and overlapping processes (reviewed in [141,142]) that result in the encapsulation of the material, thus isolating it from the surrounding tissues and, generally, negatively impacting the ability of the device to function as intended.”

What the sources say

• Not checked yetcites [141] Anderson, 2007, Phenotypic dichotomies in the foreign body reaction, Biomaterials source
• Not checked yetcites [142] Anderson, 2008, Foreign body reaction to biomaterials, Semin Immunol source

In the paper

“An increasing number of studies in the field of regenerative medicine have begun to apply these paradigms and concepts, and have shown that macrophage phenotype can be modulated by biomaterials with improved tissue remodeling and long-term functional outcomes as a result.”