Local Administration of Interleukin-1 Receptor Antagonist Improves Diabetic Wound Healing

Abstract

Impaired healing of the skin is a notable cause of patient morbidity and mortality. In diabetic individuals, dysregulated inflammation contributes to delayed wound healing. Specific immunomodulatory agents may have a role in the treatment of diabetic wounds. One of these molecules is interleukin-1 receptor antagonist (Anakinra; Amgen Corp.). Although interleukin-1 receptor antagonist (Anakinra; Amgen Corp.) is approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis and neonatal-onset multisystem inflammatory disease, little is known about the local use this drug in cutaneous wound healing. Therefore, the aim of this study is to determine the effect of locally administered interleukin-1 receptor antagonist on delayed wound healing, specifically, in a diabetic mouse model. Two 6-mm full-thickness wounds were created on the dorsa of diabetic (db/db) mice and stented. One-hour postwounding, wound margins were subcutaneously injected with either (1) low-dose interleukin-1 receptor antagonist in a gelatin-transglutaminase gel vehicle or (2) the gel vehicle only. Wounds were imaged on days 0, 7, 14, and 21 postwounding, and wound area was determined. Wound biopsies were collected on day 21 and immunohistochemically stained for neutrophil and macrophage infiltration. Wounds treated with interleukin-1 receptor antagonist had significantly smaller wound area than nontreated wounds on day 7 and day 14 postwounding. Treated wounds also showed significantly less neutrophil and macrophage infiltration. These findings support the hypothesis that interleukin-1 receptor antagonist may have an important role in cutaneous wound healing, possibly by promoting successful resolution of acute inflammation and hence accelerating wound closure. Thereby, administration of IL-1Ra may be useful in the treatment of nonhealing wounds.

Restoration of the healing microenvironment in diabetic wounds with matrix-binding IL-1 receptor antagonist

“…To evaluate the capacity of super-affinity IL-1Ra to promote wound healing, we compared the engineered antagonist to super-affinity PDGF-BB, since topical delivery of wild-type PDGF-BB is recognised to be one of the most promising strategies to promote healing of chronic wounds 47 . A previous study reported that extremely high doses (supraphysiological) of wild-type IL-1Ra (750 μg of anakinra) delivered with a gelatin-transglutaminase gel accelerated wound closure in diabetic mice 48 . Here, we found that wound treatment with a more therapeutically relevant dose of wild-type IL-1Ra (three orders of magnitude lower, 0.5 μg) delivered only once, and without a biomaterial carrier has only a marginal effect on wound closure in diabetic mice.…”

IL-1β Impaired Diabetic Wound Healing by Regulating MMP-2 and MMP-9 through the p38 Pathway

“…Mirza et al reported that IL-1β plays a key role in sustaining the proinflammatory macrophage phenotype and in impairing the healing of diabetic wounds [15]. Treatment with an inhibitor of IL-1 receptor reversed Mediators of Inflammation the impaired wound healing process in a diabetic mouse model [27]; however, the mechanism behind this effect was not elucidated. We observed that elevated levels of IL-1β in diabetic wound tissues triggers the secretion of MMPs and inhibits expression of TIMP proteins to interfere with ECM remodeling and wound closure.…”

IL-1 Family Antagonists in Mouse and Human Skin Inflammation

“…Dysregulated inflammation also contributes to delayed skin wound healing in diabetic individuals. Injection of the drug Anakinra, the recombinant human soluble IL-1Ra isoform, into wound margins of diabetic db/db mice improved wound healing and reduced neutrophil and macrophage infiltration, compared to vehicle-treated wounds ( 151 ).…”