Systemic Anti-TNFα Treatment Restores Diabetes-Impaired Skin Repair in ob/ob Mice by Inactivation of Macrophages

Goren, Itamar; Müller, Elke; Schiefelbein, Dana; Christen, Urs; Pfeilschifter, Josef; Mühl, Heiko; Frank, Stefan

doi:10.1038/sj.jid.5700842

Cited by 127 publications

(132 citation statements)

References 44 publications

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“…Studies have found that manipulating the phenotype of endogenous macrophages may be a promising therapeutic option for improving tissue repair. 28,29 In nondiabetic mice, the M1/M2 ratio peaked at day 3 and returned to baseline levels at day 10, suggesting progression to the proliferative phase of healing. In contrast, and in similarity with the proinflammatory cytokine profile, the baseline M1/M2 ratio was increased in WT diabetic mice and in NK1RKO and TAC1KO mice.…”

Section: Discussionmentioning

confidence: 96%

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Leal

Carvalho

Tellechea

et al. 2015

The American Journal of Pathology

174

155

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Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds. (Am J Pathol 2015 http://dx

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Section: Discussionmentioning

confidence: 96%

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Leal

Carvalho

Tellechea

et al. 2015

The American Journal of Pathology

174

155

View full text Add to dashboard Cite

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“…8 Imbalance in the M1/M2 ratio has been associated with cardiovascular diseases such as atherosclerosis, 9 metabolism-associated diseases such as diabetes and metabolic syndrome, 10 and autoimmune diseases such as multiple sclerosis, 11 systemic lupus erythematosus, 12 Crohn's disease 13 and rheumatoid arthritis. Persistence of M1 macrophages in the local inflammatory response can also prevent the resolution of inflammation in several chronic skin diseases, such as diabetes-associated skin ulcerations, 14 chronic venous ulcers, 15 and atopic dermatitis. 16 Targeting M1 macrophages during chronic inflammation could therefore be a promising intervention strategy to correct an imbalance between M1 and M2 macrophages, thus promoting the resolution of chronic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies

Hristodorov¹,

Mladenov²,

Felbert³

et al. 2015

mAbs

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(2015) Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies, mAbs, 7:5, 853-862, DOI: 10.1080/19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 (classical M1 or alternative M2), that play a differential role in immune regulation. In general, the M1 contribute to onset of inflammation, whereas the M2 orchestrate resolution and repair, whereby failure to switch from predominantly M1 to M2 reinforces a pro-inflammatory environment and chronic inflammation. Here, we show selective elimination of M1 macrophages in vitro by a range of CD64-targeted immunotoxins, including H22 (scFv)-ETA'. After re-polarization of already polarized macrophages, still only M1 polarization showed sensitivity toward CD64-directed immunotoxins. The selectivity for M1 was found linked to reduced endosomal protease activity in M1 macrophages as demonstrated by inhibition of endosomal proteases. Using the H22(scFv)-ETA' in a transgenic mouse model for chronic cutaneous inflammation, the M1 specificity was confirmed in vivo and a beneficial effect on inflammation demonstrated. Also ex vivo on skin biopsies from atopic dermatitis and diabetes type II patients with chronically-inflamed skin, a clear M1 specific effect was found. This indicates the potential relevance for human application. Our data show that targeting M1 macrophages through CD64 can be instrumental in developing novel intervention strategies for chronic inflammatory conditions.

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“…20,21 This reduced expression of alternatively activated macrophage markers is comparable with observations of an increased M1/M2 ratio in DB wounds of humans and mice. [22][23][24][25] Because neutrophils and macrophages play both proinflammatory and anti-inflammatory roles during the course of normal wound healing, it will be important to more fully characterize the functional and migrational time course of these cells in the DB wound.Two chemoattractants, Pf4 and CXCL2 (MIP-2), were expressed at higher levels in DB wounds. Pf4 was higher on postwounding day 5, and CXCL2 was higher on day 7.…”

mentioning

confidence: 99%

Diabetic Wounds Exhibit Decreased Ym1 and Arginase Expression with Increased Expression of IL-17 and IL-20

Finley

DeClue

Sell

et al. 2016

Advances in Wound Care

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Objective: Impaired wound healing in diabetic (DB) patients is a significant health problem; however, the roles that cytokines and innate immune cells contribute to this impaired healing are not completely understood. Approach: A mouse model was used to compare the innate immune response during DB and normal wound healing. Two 5-mm full-thickness wounds were created on the dorsal skin of BKS.Cg-m+/+Leprdb/J (DB) and C57BL/6 (wildtype) mice. Innate immune cell markers and cytokine mRNA levels were measured in wound biopsies during the first week of healing. Results: Innate immune cell influx (typified by the Gr-1 neutrophil marker and the Ym1 macrophage marker) was delayed in the DB wounds. Expression of the M2 macrophage-related genes, Ym1 and arginase 1, was significantly reduced in the DB wounds. PCR array analysis demonstrated altered cytokine expression in DB wounds. Most prominently, both interleukin (IL)-17 and IL-20 mRNA levels were significantly increased in the DB wounds. Innovation: This is the first study to identify increased levels of IL-17 and IL-20 in DB wounds. These cytokines are also elevated in the inflammatory skin disorder, psoriasis; thus, they may be potential therapeutic targets to aid in DB wound healing. Conclusion: The entire cytokine profile of DB wounds over the course of healing is not completely understood. This study suggests that the IL-17 and IL-20 families of cytokines should be further analyzed in the context of DB wound healing.Keywords: diabetes, cytokine, macrophage, wound healing INTRODUCTIONIn normal wound healing, the first cells to be recruited to the wound are the polymorphonuclear cells (PMN). These cells decontaminate the wound by phagocytosing bacteria and they release chemokines and cytokines to recruit and activate macrophages in the wound. The macrophages also phagocytose bacteria, remove damaged tissue, and produce growth factors that stimulate angiogenesis, collagen deposition, and wound closure. Notably, depletion studies have suggested important roles for both PMN and macrophages in wound healing. Depletion of PMN was shown to accelerate both normal and diabetic (DB) wound healing. 1 The consequence of macrophage depletion is dependent on the phase of healing. Selective macrophage depletion (utilizing transgenic mice expressing the diphtheria toxin receptor In addition to the phase of wound healing, the role of the macrophage may depend on the subtype of macrophage that is present in each wound. Several different phenotypes of activated macrophages have been identified, including classically activated macrophages (M1) and alternatively activated macrophages (M2) (reviewed in Refs. [3][4][5] ). The M1 macrophages kill pathogens and clean the wound by removing dying cells and debris. They can also produce proteases, which may degrade the tissue. In contrast, interleukin (IL)-4 and IL-13 activate M2 macrophages, which express the mannose receptor, L-arginase 1, dectin-1, FIZZ1, and Ym1, and decreased expression of IL-1, IL-6, and tumor necrosis factor (TNF)-a.4,...

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Systemic Anti-TNFα Treatment Restores Diabetes-Impaired Skin Repair in ob/ob Mice by Inactivation of Macrophages

Cited by 127 publications

References 44 publications

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies

Diabetic Wounds Exhibit Decreased Ym1 and Arginase Expression with Increased Expression of IL-17 and IL-20

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