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.

Keywords: IL-10; T lymphocytes; dermal scarring; extracellular matrix; fetal wound healing; hyaluronan; inflammation.

FIGURE 1

Wound healing phenotype in response to IL-10. The overexpression of interleukin (IL)-10 was accomplished using an adenoviral vector in mouse dermal wounds. Compared to PBS treated controls, IL-10 reduced scar formation. After 21 days, PBS led to the formation of a dense collagen matrix with well defined scar (A), whereas IL-10 prevented formation of a defined scar (B). At 90 days, the PBS treated wound shows mature scar tissue that is distinct from the surrounding skin (C). IL-10 led to the generation of elements of dermal tissue, with reticular collagen and hair follicles, similar to surrounding uninjured tissue (D). E, epidermis, D, dermis, *, hair follicle, PC, panniculus carnosus. The black dotted line indicates the separation between the dermis and deeper structures. The black solid line indicates scar. Images from Gordon et al. (2008), with permission.

FIGURE 2

Distribution of hyaluronan (HA) in pericellular matrix (PCM) of fibroblasts in the presence of IL-10. Phase contrast imaging of fibroblasts shows differences in PCM area between fetal and adult fibroblasts. White dotted lines indicate the border of the PCM. Green dotted lines indicate the border of the cell body. Around fetal fibroblasts, there is a dense HA PCM (A), which significantly decreases in the presence of hyaluronidase (B) or the absence of IL-10 (C). In adult fibroblasts, the HA matrix is typically smaller (D), but increases to a size similar to that of the fetal fibroblast in the presence of IL-10 (E). This effect is reversed by the presence of hyaluronidase (F). The quantification of the area of HA rich PCM relative to the area of the cell in adult and fetal fibroblasts is shown in (G). (H) Demonstrates the pathways by which IL-10 increases the HA PCM. FFB, fetal fibroblast; AFB, adult fibroblast; HAS, hyaluronan synthase; HYAL, hyaluronidase; 4-MU, 4-methylumbelliferone. **p < 0.01; scale bar, 50 μm (A–F). Figure from Balaji et al. (2017), with permission.

FIGURE 3

Relationship between T lymphocytes and scarring in severe combined immune deficient (SCID) mice. IHC images (A) and quantification (B) of CD45⁺ leukocytes and F4/80⁺ macrophages show changes in their levels after the introduction of total lymphocytes, CD4^– lymphocytes, CD4⁺CD25^– lymphocytes, and CD4⁺CD25⁺ lymphocytes. Similar changes with the introduction of T lymphocytes were seen in collagen content and the presence of myofibroblasts in the trichrome and α-SMA stained tissue, respectively (C,D). Generally, a reduction in pro-inflammatory/pro-fibrotic cells and collagen deposition was observed after the introduction of specific T cell subsets. There was also an increase in microvascularization after the introduction of particular lymphocyte subsets (E,F). *p < 0.05; scale bars, 75 μm (A), 200 μm (C,F). Figure from Wang et al. (2019), with permission.

FIGURE 4

Signaling and cellular regulation pathways involved in fibrotic and regenerative healing. In fibrotic healing, inflammatory signals, including IL-6 and IL-8 activate M1 macrophages to propagate the inflammatory response, activate effector T cells, and recruit fibroblasts to deposit collagen. This is supported by low molecular weight (LMW) HA. Regenerative healing is characterized by reduced inflammation due to the presence of IL-10, HMW HA, and Tregs. IL-10 induces fibroblasts to secrete HMW HA, which results in the increased presence of Tregs and reduced inflammatory macrophage polarization and collagen deposition.