The Role of an IL-10/Hyaluronan Axis in Dermal Wound Healing

Abstract

Scar formation is the typical endpoint of postnatal dermal wound healing, which affects more than 100 million individuals annually. Not only do scars cause a functional burden by reducing the biomechanical strength of skin at the site of injury, but they also significantly increase healthcare costs and impose psychosocial challenges. Though the mechanisms that dictate how dermal wounds heal are still not completely understood, they are regulated by extracellular matrix (ECM) remodeling, neovascularization, and inflammatory responses. The cytokine interleukin (IL)-10 has emerged as a key mediator of the pro- to anti-inflammatory transition that counters collagen deposition in scarring. In parallel, the high molecular weight (HMW) glycosaminoglycan hyaluronan (HA) is present in the ECM and acts in concert with IL-10 to block pro-inflammatory signals and attenuate fibrotic responses. Notably, high concentrations of both IL-10 and HMW HA are produced in early gestational fetal skin, which heals scarlessly. Since fibroblasts are responsible for collagen deposition, it is critical to determine how the concerted actions of IL-10 and HA drive their function to potentially control fibrogenesis. Beyond their independent actions, an auto-regulatory IL-10/HA axis may exist to modulate the magnitude of CD4 + effector T lymphocyte activation and enhance T regulatory cell function in order to reduce scarring. This review underscores the pathophysiological impact of the IL-10/HA axis as a multifaceted molecular mechanism to direct primary cell responders and regulators toward either regenerative dermal tissue repair or scarring.

Mechanistic Actions of microRNAs in Diabetic Wound Healing

“…Following injury, proliferating fibroblasts migrate in high abundance to the wound site, predominantly due to their stimulation by TGF-β and PDGF. In addition, they secrete extra cellular matrix (ECM) proteins (hyaluronan, fibronectins and proteoglycans) and subsequently produce collagen and fibronectin [ 33 ]. The provisional matrix, which replaces the clot at the site of a wound, is termed granulation tissue, which fills the wound space providing the scaffolding spot for migrating fibroblasts that differentiate into myofibroblasts and are responsible for collagen production at the wound site ( Figure 1 ) [ 34 ].…”

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa

“…We found upregulation of the FCGR1A (log 2 FC = 1.28, p = 5.09E-24) and FCGR1B (log 2 FC = 0.732, p = 1.97E-9) genes, which encode for FcγRI (CD64), a receptor upregulated on M1 macrophages in chronic inflammatory diseases ( Figures 5A,B , and Table 1 ) ( 55 ). Impaired efferocytosis prevents M2 macrophages from producing anti-inflammatory cytokines such as IL-10 (not differentially expressed in HS sample), which is required for normal wound healing ( 66 ). As expected, genes associated with M2 macrophage phagocytosis of apoptotic cells were downregulated in the HS sample, including CD163 (log 2 FC = −1.23, p = 3.46E-44) and CD209 (log 2 FC = −0.715, p = 5.74E-36) ( Figure 3 ) ( 52 , 67 ).…”

Immunologic Roles of Hyaluronan in Dermal Wound Healing

“…This is significant as mast cells express and secrete the anti-inflammatory cytokine IL-10 [48], which has been associated with scarless wound healing and regeneration [49]. IL-10 in turn stimulates fibroblasts to secrete HMW-HA to prevent collagen deposition and inflammatory macrophage polarization [4].…”

“…Each year, more than 100 million people in developed countries are expected to develop scars from irregular wound healing outcomes, adding physical, financial, and psychosocial burdens to the problem [1]. Many research groups believe that the inflammation stage of wound healing plays a decisive role in modulating wound healing [2][3][4]. However, the recipe of successful wound healing is unclear due to the complexity of the immune system and the role of hyaluronan, a prolific glycosaminoglycan found in the extracellular matrix (ECM), which influences the inflammation stage of wound healing.…”