Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice

Wound-conditioned medium from chronic wounds of diabetic humans increases release of IL-1β and IL-18 from cultured human blood-derived Mp.

“Wound-conditioned medium increased release of IL-1β and IL-18 into the medium surrounding cultured Mp (Fig. 3A and B).”

Active caspase-1 is detected in 10.5 ± 1.3% of conditioned medium-stimulated human Mp versus 2.9 ± 0.7% of nonstimulated control cells.

“active caspase-1 was detected in 2.9 ± 0.7% of nonstimulated control cells and in 10.5 ± 1.3% of conditioned medium–stimulated cells.”

Mp are the dominant producers of IL-1β and IL-18 after wounding in both db/+ and db/db mice.

“When different wound cell populations were compared, Mp were the dominant producers of IL-1β and IL-18 after wounding in both db/+ and db/db mice (Fig. 2C and D).”

No difference was observed in Mp expression of NLRP-3 or caspase-1 on days 5 and 10 postinjury in either db/+ or db/db mice.

“although no difference was observed in Mp expression of NLRP-3 or caspase-1 on days 5 and 10 postinjury in either db/+ or db/db mice (Fig. 2I and J)”

Mp isolated from chronic wounds of diabetic humans express low levels of PI-9 and caspase-12.

“Mp isolated from chronic wounds expressed high levels of inflammasome components NLRP-3 and caspase-1, and inflammasome targets IL-1β and IL-18, but only low levels of proteinase inhibitor-9 (PI-9) and caspase-12, which are negative regulators of inflammasome activity (Fig. 1A–F).”

The caspase-1 inhibitor YVAD and the inflammasome inhibitor glyburide reduce conditioned medium-induced release of IL-1β and IL-18 from human Mp.

“both the caspase-1 inhibitor YVAD and the inflammasome inhibitor glyburide reduced the conditioned medium–induced release of IL-1β and IL-18.”

Mp isolated from chronic wounds of diabetic humans express high levels of NLRP-3, caspase-1, IL-1β, and IL-18.

“Mp isolated from chronic wounds expressed high levels of inflammasome components NLRP-3 and caspase-1, and inflammasome targets IL-1β and IL-18, but only low levels of proteinase inhibitor-9 (PI-9) and caspase-12, which are negative regulators of inflammasome activity (Fig. 1A–F).”

Wound-conditioned medium from db/db mice induces IL-1β and IL-18 release from wild-type mouse bone marrow-derived Mp.

“Wound-conditioned medium from db/db mice induced IL-1β and IL-18 release”

Active caspase-1 is detected in a higher percentage of db/db wound Mp than db/+ wound Mp (9.9 ± 1.4% vs 4.8 ± 1.1%).

“active caspase-1 was detected in 4.8 ± 1.1% of db/+ wound Mp and in 9.9 ± 1.4% of db/db wound Mp (mean ± SD).”

Wound-conditioned medium downregulates expression of NLRP-3, caspase-1, PI-9, and caspase-12 in cultured Mp.

“Interestingly, wound-conditioned medium downregulated expression of NLRP-3, caspase-1, PI-9, and caspase-12”

Conditioned medium from noninjured db/db skin does not induce IL-1β or IL-18 release from cultured Mp.

“noninjured skin–conditioned medium did not induce IL-1β or IL-18 release from cultured Mp (data not shown).”

Inhibiting inflammasome activity in wounds of db/db mice induces a switch from proinflammatory to healing-associated Mp phenotypes.

“induced a switch from proinflammatory to healing-associated Mp phenotypes”

Topical treatment with glyburide or YVAD does not change body weight or blood glucose levels in db/db mice compared with vehicle-treated mice.

“Mice whose wounds were treated with glyburide or YVAD showed no change in body weight or blood glucose levels compared with vehicle-treated mice (Supplementary Table 2).”

YVAD and glyburide reduce db/db wound-conditioned medium-induced cytokine release from wild-type mouse Mp.

“both YVAD and glyburide reduced cytokine release (Fig. 3E and F).”

IL-1β blocking antibody inhibits the induction and release of IL-1β and IL-18 from cultured Mp treated with db/db wound-conditioned medium.

“Wound-conditioned medium upregulated expression and release of IL-1β and IL-18, and the IL-1β blocking antibody inhibited the induction and release of these cytokines (Fig. 5A, B, G, and H).”

Topical treatment with glyburide or YVAD increases granulation tissue formation in db/db mice.

“Treatment with glyburide or YVAD accelerated re-epithelialization and increased granulation tissue formation (Fig. 6A–D)”

Treatment with either glyburide or YVAD reduces IL-1β levels in wound homogenates of db/db mice.

“As expected, treatment with either glyburide or YVAD reduced levels of IL-1β and IL-18 in wound homogenates (Fig. 6G and H)”

Treatment with either glyburide or YVAD reduces IL-18 levels in wound homogenates of db/db mice.

“As expected, treatment with either glyburide or YVAD reduced levels of IL-1β and IL-18 in wound homogenates (Fig. 6G and H)”

Topical treatment with glyburide or YVAD accelerates re-epithelialization in db/db mice.

“Treatment with glyburide or YVAD accelerated re-epithelialization and increased granulation tissue formation (Fig. 6A–D)”

Antioxidants NAC and DPI reduce IL-1β and IL-18 release from cultured Mp.

“We next inhibited ROS production using the antioxidants NAC and DPI (Fig. 4B–D) and found that such treatment reduced IL-1β and IL-18 release.”

Neither glyburide nor YVAD treatment influences angiogenesis as assessed by CD31 labeling in db/db mice.

“Whereas neither glyburide nor YVAD treatment influenced angiogenesis as assessed by CD31 labeling (Fig. 6F)”

Wound-conditioned medium-treated IL-1R1 knockout macrophages exhibit blunted downregulation of PI-9 compared with wild-type macrophages.

“blunted downregulation of PI-9 and caspase-12 (Fig. 5M and N)”

Glyburide and YVAD treatment increase wound levels of IGF-1 in db/db mice.

“In contrast, wound levels of IGF-1 and TGF-β were increased both by glyburide and by YVAD treatment (Fig. 6K and L)”

Wound-conditioned medium-treated IL-1R1 knockout macrophages exhibit blunted upregulation of IL-1β expression and release compared with wild-type macrophages.

“compared with wild-type Mp, wound-conditioned medium–treated IL-1R1 knockout Mp exhibited blunted upregulation of IL-1β and IL-18 expression and release (Fig. 5I, J, O, and P)”

Conditioned medium from day 5 wounds of both db/+ and db/db mice increases DCF fluorescence in cultured Mp above medium-only controls.

“Conditioned medium from day 5 wounds of both db/+ and db/db mice increased DCF fluorescence in cultured Mp above medium-only controls (Fig. 4A).”

Inhibiting inflammasome activity in wounds of db/db mice increases levels of prohealing growth factors.

“increased levels of prohealing growth factors”

Cytokine release is absent from NLRP-3 and caspase-1-null Mp stimulated with db/db wound-conditioned medium.

“cytokine release was absent from NLRP-3 and caspase-1–null Mp (Fig. 3G and H).”

ROS induction by wound-conditioned medium parallels IL-1β and IL-18 production from cultured Mp.

“Thus, ROS induction by wound-conditioned medium paralleled IL-1β and IL-18 production from cultured Mp.”

Topical application of pharmacological inhibitors of inflammasome activity improves healing of wounds in db/db mice.

“inhibiting inflammasome activity in wounds of db/db mice using topical application of pharmacological inhibitors improved healing of these wounds”

Wound-conditioned medium-treated IL-1R1 knockout macrophages exhibit blunted upregulation of IL-18 expression and release compared with wild-type macrophages.

“compared with wild-type Mp, wound-conditioned medium–treated IL-1R1 knockout Mp exhibited blunted upregulation of IL-1β and IL-18 expression and release (Fig. 5I, J, O, and P)”

Wound-conditioned medium-treated IL-1R1 knockout macrophages exhibit blunted downregulation of caspase-12 compared with wild-type macrophages.

“blunted downregulation of PI-9 and caspase-12 (Fig. 5M and N)”

Macrophages from glyburide-treated wounds exhibit increased TGF-β expression compared with DMSO-treated wounds.

“as was expression of IGF-1, TGF-β, IL-10, and CD206 (Fig. 6S–V).”

Macrophages from glyburide-treated wounds exhibit increased CD206 expression compared with DMSO-treated wounds.

“as was expression of IGF-1, TGF-β, IL-10, and CD206 (Fig. 6S–V).”

Bone marrow transfer from NLRP-3-null or caspase-1-null mice reduces IL-6 levels in wounds of db/db mice.

“These bone marrow transfers also reduced levels of TNF-α and IL-6 (Fig. 7I and J)”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Bone marrow transfer from NLRP-3-null or caspase-1-null mice reduces IL-1β levels in wound homogenates of db/db mice.

“Furthermore, bone marrow transfer from NLRP-3–null or caspase-1–null mice to db/db mice resulted in reduced levels of IL-1β and IL-18 in wound homogenates (Fig. 7G and H)”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Transfer of NLRP-3- or caspase-1-null bone marrow increases wound levels of TGF-β in db/db mice.

“In contrast, wound levels of IGF-1 and TGF-β were increased by transfer of both NLRP-3– and capase-1–null bone marrow (Fig. 7K and L)”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Macrophages from glyburide-treated wounds exhibit increased IL-6 expression compared with DMSO-treated wounds.

“although expression of IL-6 was increased (Fig. 6R)”

Macrophages from glyburide-treated wounds exhibit increased IL-10 expression compared with DMSO-treated wounds.

“as was expression of IGF-1, TGF-β, IL-10, and CD206 (Fig. 6S–V).”

Macrophages from glyburide-treated wounds exhibit increased IGF-1 expression compared with DMSO-treated wounds.

“as was expression of IGF-1, TGF-β, IL-10, and CD206 (Fig. 6S–V).”

Bone marrow transfer from NLRP-3-null or caspase-1-null mice reduces IL-18 levels in wound homogenates of db/db mice.

“Furthermore, bone marrow transfer from NLRP-3–null or caspase-1–null mice to db/db mice resulted in reduced levels of IL-1β and IL-18 in wound homogenates (Fig. 7G and H)”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Macrophages from glyburide-treated wounds exhibit lower IL-1β expression than macrophages from DMSO-treated wounds.

“Compared with Mp from DMSO-treated wounds, Mp from glyburide-treated wounds exhibited lower-level expression of IL-1β, IL-18, and TNF-α (Fig. 6O–Q)”

Transfer of NLRP-3- or caspase-1-null bone marrow increases wound levels of IGF-1 in db/db mice.

“In contrast, wound levels of IGF-1 and TGF-β were increased by transfer of both NLRP-3– and capase-1–null bone marrow (Fig. 7K and L)”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Transfer of bone marrow from either NLRP-3- or caspase-1-null mice does not influence angiogenesis in db/db mice.

“Although transfer of bone marrow from either NLRP-3– or caspase-1–null mice did not influence angiogenesis (Fig. 7F)”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Bone marrow transfer from NLRP-3-null or caspase-1-null mice reduces TNF-α levels in wounds of db/db mice.

“These bone marrow transfers also reduced levels of TNF-α and IL-6 (Fig. 7I and J)”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Bone marrow transfer from wild-type to db/db mice results in wound healing similar to db/db mice that had not received bone marrow transfer.

“Bone marrow transfer from wild-type to db/db mice resulted in wound healing that was similar to db/db mice that had not received bone marrow transfer (compare Fig. 7A–D with Fig. 6A–D and refs. 14,15)”

• cites [14] Mirza, 2011, Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice, Cytokine sourceNot checked yet

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• cites [15]Not checked yet

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Transfer of NLRP-3-null but not caspase-1-null bone marrow results in increased collagen deposition in db/db mice.

“In addition, transfer of NLRP-3–null but not caspase-1–null bone marrow resulted in increased collagen deposition (Fig. 7E).”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Transfer of NLRP-3- or caspase-1-null bone marrow increases granulation tissue formation in db/db mice.

“In contrast, transfer of NLRP-3– or caspase-1–null bone marrow resulted in accelerated re-epithelialization and increased granulation tissue formation, mimicking the effects of the inflammasome inhibitors (Fig. 7A–D).”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Glyburide and YVAD treatment increase wound levels of TGF-β in db/db mice.

“In contrast, wound levels of IGF-1 and TGF-β were increased both by glyburide and by YVAD treatment (Fig. 6K and L)”

Macrophages from glyburide-treated wounds exhibit lower IL-18 expression than macrophages from DMSO-treated wounds.

“Compared with Mp from DMSO-treated wounds, Mp from glyburide-treated wounds exhibited lower-level expression of IL-1β, IL-18, and TNF-α (Fig. 6O–Q)”

Macrophages from glyburide-treated wounds exhibit lower TNF-α expression than macrophages from DMSO-treated wounds.

“Compared with Mp from DMSO-treated wounds, Mp from glyburide-treated wounds exhibited lower-level expression of IL-1β, IL-18, and TNF-α (Fig. 6O–Q)”

After transfer of NLRP-3- or caspase-1-null bone marrow, α-smooth-muscle actin staining is increased in db/db mice.

“in both cases, α-smooth-muscle actin staining was increased (Supplementary Fig. 2).”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Transfer of NLRP-3- or caspase-1-null bone marrow accelerates re-epithelialization in db/db mice.

“In contrast, transfer of NLRP-3– or caspase-1–null bone marrow resulted in accelerated re-epithelialization and increased granulation tissue formation, mimicking the effects of the inflammasome inhibitors (Fig. 7A–D).”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Caspase-12 is upregulated in macrophages as they switch from a proinflammatory to a prohealing phenotype in nondiabetic mice.

“We found that PI-9 and caspase-12 are upregulated in Mp as they switch from a proinflammatory to a prohealing phenotype in nondiabetic mice”

Upregulation of the inflammasome inhibitors PI-9 and caspase-12 is impaired in diabetic mice.

“but that both the upregulation of these inflammasome inhibitors and the Mp phenotypic switch are impaired in diabetic mice.”

PI-9 is upregulated in macrophages as they switch from a proinflammatory to a prohealing phenotype in nondiabetic mice.

“We found that PI-9 and caspase-12 are upregulated in Mp as they switch from a proinflammatory to a prohealing phenotype in nondiabetic mice”

Macrophages isolated from chronic human diabetic wounds exhibit only low-level expression of PI-9 and caspase-12.

“In addition, Mp isolated from chronic human diabetic wounds exhibited only low-level expression of PI-9 and caspase-12.”

The macrophage phenotypic switch is impaired in diabetic mice.

“but that both the upregulation of these inflammasome inhibitors and the Mp phenotypic switch are impaired in diabetic mice.”

During wound healing, activity of the inflammasome may be regulated at least in part by expression of its endogenous inhibitors.

“These data indicate that, during wound healing, activity of the inflammasome may be regulated at least in part by expression of its endogenous inhibitors.”

Proinflammatory danger signals induce activity of the NLRP-3 inflammasome.

“Proinflammatory danger signals induce activity of a multiprotein complex called the Nod-like receptor protein (NLRP)-3 inflammasome (16–18).”

• cites [16] Martinon, 2009, The inflammasomes: guardians of the body, Annu Rev Immunol sourceNot checked yet

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• cites [17] Strowig, 2012, Inflammasomes in health and disease, Nature sourceNot checked yet

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• cites [18] Pedra, 2009, Sensing pathogens and danger signals by the inflammasome, Curr Opin Immunol sourceNot checked yet

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The persistence of the proinflammatory Mp phenotype appears to be mediated at least in part by IL-1β.

“the persistence of the proinflammatory Mp phenotype appears to be mediated at least in part by the proinflammatory cytokine interleukin (IL)-1β (15).”

• cites [15]Not checked yet

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The inflammasome may represent a new therapeutic target for improving healing in diabetic individuals.

“the inflammasome may represent a new therapeutic target for improving healing in diabetic individuals.”

• AssumptionRests on an assumption: The db/db mouse model of type 2 diabetes is representative of human diabetic wound healing for testing inflammasome-targeted therapies.

Elevated levels of IL-1β have been found in wounds of diabetic humans and mice.

“Elevated levels of IL-1β have been found in wounds of diabetic humans and mice (12,15,19,20)”

• cites [12] Goren, 2003, Leptin and wound inflammation in diabetic ob/ob mice: differential regulation of neutrophil and macrophage influx and a potential role for the scab as a sink for inflammatory cells and mediators, Diabetes sourceNot checked yet

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• cites [15]Not checked yet

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• cites [19] Mast, 1996, Interactions of cytokines, growth factors, and proteases in acute and chronic wounds, Wound Repair Regen sourceNot checked yet

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• cites [20] Trengove, 1999, Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors, Wound Repair Regen sourceNot checked yet

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Sustained inflammasome activity in wound Mp contributes to impaired early healing responses of diabetic wounds.

“Our findings indicate that sustained inflammasome activity in wound Mp contributes to impaired early healing responses of diabetic wounds”

Blocking inflammasome activity in bone marrow cells is sufficient to improve healing in db/db mice.

“data generated from bone marrow–transfer experiments from NLRP-3 or caspase-1 knockout to db/db mice indicated that blocking inflammasome activity in bone marrow cells is sufficient to improve healing.”

Wound-conditioned medium-induced IL-1β and IL-18 release appears to be mediated by the NLRP-3 inflammasome.

“Thus, wound-conditioned medium–induced IL-1β and IL-18 release appears to be mediated by the NLRP-3 inflammasome.”

IL-1R1 knockout macrophages are less sensitive to wound-conditioned medium-induced inflammasome activity than wild-type macrophages.

“These data indicate that IL-1R1 knockout Mp are less sensitive to wound-conditioned medium–induced inflammasome activity than are wild-type Mp.”

IL-1β is known to induce a proinflammatory Mp phenotype.

“Since IL-1β, in turn, is known to induce a proinflammatory Mp phenotype (15,21)”

• cites [15]Not checked yet

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• cites [21] Dinarello, 2009, Immunological and inflammatory functions of the interleukin-1 family, Annu Rev Immunol sourceNot checked yet

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The diabetic wound environment activates the inflammasome at least partly by increasing ROS production.

“In total, these data indicate that the diabetic wound environment activates the inflammasome at least partly by increasing ROS production.”

The increased α-smooth-muscle actin staining indicates increased myofibroblasts.

“indicating increased myo-fibroblasts (Supplementary Fig. 1).”

The reduction in IL-1β and IL-18 levels is consistent with reduced activity of the NLRP-3 inflammasome and caspase-1.

“consistent with reduced activity of the NLRP-3 inflammasome and caspase-1.”

IL-1β itself contributes to the initial signal in inflammasome activation in cultured Mp.

“Wound-conditioned medium upregulated expression and release of IL-1β and IL-18, and the IL-1β blocking antibody inhibited the induction and release of these cytokines (Fig. 5A, B, G, and H).”

Mp exhibit a sustained proinflammatory phenotype in wounds of diabetic mice.

“We recently demonstrated that Mp exhibit a sustained proinflammatory phenotype in wounds of diabetic mice (14)”

• cites [14] Mirza, 2011, Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice, Cytokine sourceNot checked yet

  Not checked in the free run.

Bone marrow-derived NLRP-3 inflammasome produces the majority of IL-1β and IL-18 in wounds of diabetic mice.

“indicating that bone marrow–derived NLRP-3 inflammasome produces the majority of IL-1β and IL-18 in these wounds.”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

The effects of NLRP-3- or caspase-1-null bone marrow transfer mimic the effects of inflammasome inhibitors.

“mimicking the effects of the inflammasome inhibitors”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Impaired healing in db/db mice is not a result of intrinsic defects in db/db macrophages.

“indicating that impaired healing is not a result of intrinsic defects in db/db Mp.”

Targeting the inflammasome may provide a novel target for improving healing in diabetic patients.

“our data indicate that targeting the inflammasome may provide a novel target for improving healing in diabetic patients.”

The increased IGF-1 and TGF-β indicate a more prohealing wound environment.

“indicating a more prohealing wound environment.”

In vitro studies indicated that the diabetic wound environment is sufficient to activate the inflammasome in cultured macrophages via an ROS-mediated pathway.

“In vitro studies indicated that the diabetic wound environment is sufficient to activate the inflammasome in cultured Mp via an ROS-mediated pathway”

The NLRP-3 inflammasome is a key regulatory pathway in the chronic inflammatory response in wounds of diabetic humans and mice.

“The major novel finding of this study is that the NLRP-3 inflammasome is a key regulatory pathway in the chronic inflammatory response in wounds of diabetic humans and mice.”

The downstream target IL-1β participates in a proinflammatory positive-feedback loop that contributes to the persistent inflammatory response.

“and that its downstream target IL-1β participates in a proinflammatory positive-feedback loop that contributes to the persistent inflammatory response (Fig. 8).”

A persistent proinflammatory wound macrophage phenotype has been observed in diabetic humans and mice and in chronic venous ulcers.

“We and others have observed a persistent proinflammatory wound Mp phenotype in diabetic humans and mice (14,29) and in chronic venous ulcers (30).”

• cites [14] Mirza, 2011, Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice, Cytokine sourceNot checked yet

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• cites [29] Rodero, 2013, Reduced Il17a expression distinguishes a Ly6c(lo)MHCII(hi) macrophage population promoting wound healing, J Invest Dermatol sourceNot checked yet

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• cites [30] Sindrilaru, 2011, An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice, J Clin Invest sourceNot checked yet

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The increased IGF-1 and TGF-β indicate induction of a more prohealing wound environment.

“indicating the induction of a more prohealing wound environment.”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

The reduction in TNF-α and IL-6 indicates additional downregulation of the proinflammatory wound environment.

“indicating additional downregulation of the proinflammatory wound environment.”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Topical glyburide improves wound healing in diabetic mice.

“In our studies, topical glyburide improved wound healing in diabetic mice”

Macrophages are the dominant producers of IL-1β in wounds of diabetic mice.

“However, our studies also indicate that Mp are the dominant producers of IL-1β in wounds of diabetic mice”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

Loss of bone marrow cell-derived inflammasome activity is sufficient to reduce IL-1β and IL-18 levels in the wounds of diabetic mice.

“and our bone marrow–transfer experiments indicate that loss of bone marrow cell–derived inflammasome activity is sufficient to reduce IL-1β and IL-18 levels in the wounds of diabetic mice.”

• AssumptionRests on an assumption: Bone marrow transfer from donor mice to db/db mice specifically targets the inflammasome in macrophages.

The bone marrow-transfer experiments do not distinguish the role of caspase-1 and caspase-11 in the impaired healing of wounds in db/db mice.

“and so our bone marrow–transfer experiments do not distinguish the role of these caspases in the impaired healing of wounds in db/db mice.”

A limitation of the study is that the caspase-1-null mice were also found to be deficient in caspase-11.

“A limitation of our study is that the caspase-1–null mice were also found to be deficient in caspase-11 (46,47)”

• cites [46] Kayagaki, 2011, Non-canonical inflammasome activation targets caspase-11, Nature sourceNot checked yet

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• cites [47] Broz, 2012, Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1, Nature sourceNot checked yet

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The NLRP-3 inflammasome plays an important role in the impaired healing of wounds in db/db mice.

“Nonetheless, our experiments indicate that the NLRP-3 inflammasome plays an important role in the impaired healing of these wounds.”