Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes

Abstract

Background: Impaired wound healing is the most common and significant complication of Diabetes. While most other complications of Diabetes have better treatment options, diabetic wounds remain a burden as they can cause pain and suffering in patients. Wound closure and repair are orchestrated by a sequence of events aided by the release of pro-inflammatory cytokines, which are dysregulated in cases of Diabetes, making the wound environment unfavorable for healing and delaying the wound healing processes. This concise review provides an overview of the dysregulation of pro-inflammatory cytokines and offers insights into better therapeutic outcomes.

Purpose of review: Although many therapeutic approaches have been lined up nowadays to treat Diabetes, there are no proper treatment modalities proposed yet in treating diabetic wounds due to the lack of understanding about the role of inflammatory mediators, especially Pro-inflammatory mediators- Cytokines, in the process of Wound healing which we mainly focus on this review.

Recent findings: Although complications of Diabetes mellitus are most reported after years of diagnosis, the most severe critical complication is impaired Wound Healing among Diabetes patients. Even though Trauma, Peripheral Artery Disease, and Peripheral Neuropathy are the leading triggering factors for the development of ulcerations, the most significant issue contributing to the development of complicated cutaneous wounds is wound healing impairment. It may even end up with amputation. Newer therapeutic approaches such as incorporating the additives in the present dressing materials, which include antimicrobial molecules and immunomodulatory cytokines is of better therapeutic value.

Summary: The adoption of these technologies and the establishment of novel therapeutic interventions is difficult since there is a gap in terms of a complete understanding of the pathophysiological mechanisms at the cellular and molecular level and the lack of data in terms of the assessment of safety and bioavailability differences in the individuals' patients. The target-specific pro-inflammatory cytokines-based therapies, either by upregulation or downregulation of them, will be helpful in the wound healing process and thereby enhances the Quality of life in patients, which is the goal of drug therapy.

Keywords: cytokines; diabetes mellitus; pro-inflammatory; therapeutic approach; wound healing.

Figure 1

General mechanism of wound healing. Various phases of wound healing haemostasis, inflammation, proliferation and remodelling.

Figure 2

Pathogenesis of impaired wound healing in diabetes. In diabetic wounds, there is an impairment in the collagen synthesis thereby decreasing the solubility of the Extracellular matrix promoting increased inflammatory response by the release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α in inflammatory phase. Whereas in proliferative phase, impairment in angiogenesis and vasculogenesis and in remodeling phase increased MMP leads to degradation of ECM thereby resulting in impaired wound healing. (IL – Interleukin, TNF- Tumor Necrosis Factor, MMP- Matrix Metalloproteinase, ECM- Extracellular Matrix).

Figure 3

Pathogenesis of impaired wound healing involving IL-1β. Blood Monocytes and Tissue Macrophages synthesize the IL-1β which activates the secretory lysosomes and resulting in the Caspase- 1 cleavage through IL-1β and GSDMD which in turn results with increased insulin resistance thereby delays the process of wound healing. (IL – Interleukin, GSDMD - protein gasdermin D).

Figure 4

Pathogenesis of impaired wound healing involving IL-6. T- Cells and Macrophages secretes the IL-6. Over production or elevated IL-6 levels increases the insulin resistance, Synthesized IL-6 may also generate the B-cell mediated immune response, recruiting more neutrophils to the wound site and also promote the release of IL-8 and MCP thereby recruiting more inflammatory cells to wound site delaying the process of wound healing. (IL – Interleukin, MCP – Monocyte Chemoattractant Protein).

Figure 5

IL-17 mechanism of wound healing. IL- 17 has been sub classified as IL-17A, 17C and 17F. IL-17A and 17C binds with IL-17RA/RC forming the receptor complex in turn activates the act-1 gene activates NF-kB pathway of inflammation thereby prolonging the inflammatory phase delaying the wound healing phase. IL-17F acting on the keratinocytes produces neutrophils prolonging inflammatory phase and delaying the process of wound healing. (IL – Interleukins, NF-kB - Nuclear factor kappa B).