Blocking Interleukin-1β Induces a Healing-Associated Wound Macrophage Phenotype and Improves Healing in Type 2 Diabetes

Abstract

Diabetes is associated with persistent inflammation and defective tissue repair responses. The hypothesis of this study was that interleukin (IL)-1β is part of a proinflammatory positive feedback loop that sustains a persistent proinflammatory wound macrophage phenotype that contributes to impaired healing in diabetes. Macrophages isolated from wounds in diabetic humans and mice exhibited a proinflammatory phenotype, including expression and secretion of IL-1β. The diabetic wound environment appears to be sufficient to induce these inflammatory phenomena because in vitro studies demonstrated that conditioned medium of both mouse and human wounds upregulates expression of proinflammatory genes and downregulates expression of prohealing factors in cultured macrophages. Furthermore, inhibiting the IL-1β pathway using a neutralizing antibody and macrophages from IL-1 receptor knockout mice blocked the conditioned medium–induced upregulation of proinflammatory genes and downregulation of prohealing factors. Importantly, inhibiting the IL-1β pathway in wounds of diabetic mice using a neutralizing antibody induced a switch from proinflammatory to healing-associated macrophage phenotypes, increased levels of wound growth factors, and improved healing of these wounds. Our findings indicate that targeting the IL-1β pathway represents a new therapeutic approach for improving the healing of diabetic wounds.

Lysosomes Integrate Metabolic-Inflammatory Cross-talk in Primary Macrophage Inflammasome Activation

“…Macrophage dysfunction is highly relevant to the complications of obesity and diabetes, which are frequently associated with prolonged inflammation and impaired resolution/repair. The inflammasome has been linked to this disease phenotypes (31). Our data add to the mechanistic understanding of how lipids modulate macrophage biology to affect inflammation.…”

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

“…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.…”

Drug delivery strategies to control macrophages for tissue repair and regeneration

“…Similarly, temporal control over the administration of anti-inflammatory therapies may lead to positive outcomes. For example, Mirza et al 34 showed that the delivery of an inhibitor of the inflammatory cytokine interleukin-1-beta (IL1b) improved healing of diabetic ulcers when it was applied at three days post wounding. However, more studies are required to systematically evaluate the influence of timing of administration of proand anti-inflammatory therapeutics.…”