Macrophage Dysregulation and Impaired Skin Wound Healing in Diabetes

Abstract

Monocytes (Mo) and macrophages (Mϕ) play important roles in normal skin wound healing, and dysregulation of wound Mo/Mϕ leads to impaired wound healing in diabetes. Although skin wound Mϕ originate both from tissue resident Mϕ and infiltrating bone marrow-derived Mo, the latter play dominant roles during the inflammatory phase of wound repair. Increased production of bone marrow Mo caused by alterations of hematopoietic stem and progenitor cell (HSPC) niche and epigenetic modifications of HSPCs likely contributes to the enhanced number of wound Mϕ in diabetes. In addition, an impaired transition of diabetic wound Mϕ from "pro-inflammatory" to "pro-healing" phenotypes driven by the local wound environment as well as intrinsic changes in bone marrow Mo is also thought to be partly responsible for impaired diabetic wound healing. The current brief review describes the origin, heterogeneity and function of wound Mϕ during normal skin wound healing followed by discussion of how dysregulated wound Mϕ numbers and phenotype are associated with impaired diabetic wound healing. The review also highlights the possible links between altered bone marrow myelopoiesis and increased Mo production as well as extrinsic and intrinsic factors that drive wound macrophage dysregulation leading to impaired wound healing in diabetes.

Keywords: bone marrow; diabetes; hematopoietic stem; inflammation; macrophages; monocytes; progenitor cells; wound healing.

FIGURE 1

Mo/Mϕ dysregulation in diabetic wound. (A) High numbers of bone marrow-produced Mo may lead to increased number of diabetic wound Mϕ. (B) Mϕ transition from M1- to M2-like phenotypes is impaired in diabetic wounds resulting in increased accumulation of M1-like wound Mϕ. (C) Decreased PPAR-γ and increased RAGE signaling reduce the phagocytic ability of wound Mϕ decreasing phagocytosis of apoptotic neutrophils and necrotic debris thus leading to increased accumulation of neutrophils and necrotic debris in diabetic wounds.

FIGURE 2

Potential mechanisms of alterations in bone marrow-derived Mo and in wound Mϕ in diabetes. (A) Low-grade chronic inflammation caused by metabolic stress induces myeloid bias in diabetic HSCs leading to increased production of Mo. In addition, intrinsic modifications of HSCs caused by epigenetic changes such as hypermethylation of Notch1, PU.1, and Klf4 genes and H3K27me3 repressive methylation of IL-12 gene can be passed down to Mo altering their phenotype. (B) Increased levels of IL-1β, MCP-1, AGE, DAMPs, and other inflammatory cytokines and chemokines in wound microenvironment induce NLRP3 and IL-1R1 signaling and other inflammatory pathways in wound Mϕ leading to dysregulated polarization of Mϕ from M1 to M2-like phenotype in diabetic wounds.