The role of nuclear hormone receptors in cutaneous wound repair

Abstract

The cutaneous wound repair process involves balancing a dynamic series of events ranging from inflammation, oxidative stress, cell migration, proliferation, survival and differentiation. A complex series of secreted trophic factors, cytokines, surface and intracellular proteins are expressed in a temporospatial manner to restore skin integrity after wounding. Impaired initiation, maintenance or termination of the tissue repair processes can lead to perturbed healing, necrosis, fibrosis or even cancer. Nuclear hormone receptors (NHRs) in the cutaneous environment regulate tissue repair processes such as fibroplasia and angiogenesis. Defects in functional NHRs and their ligands are associated with the clinical phenotypes of chronic non-healing wounds and skin endocrine disorders. The functional relationship between NHRs and skin niche cells such as epidermal keratinocytes and dermal fibroblasts is pivotal for successful wound closure and permanent repair. The aim of this review is to delineate the cutaneous effects and cross-talk of various nuclear receptors upon injury towards functional tissue restoration.

Keywords: hormones; innervation; keratinocytes; nuclear receptors; regeneration; tissue repair; vitamin D; wound healing.

Figure 1

Overlapping phases of skin wound healing in humans. The major phases of wound healing are marked by inflammation, tissue formation/proliferation and tissue remodelling. Image inserts, normal skin healing after an abrasion in a 3-year-old patient. Left insert, approximately 5 days after abrasion. Right insert, approximately 8 weeks after abrasion. Abbreviation: ECM, extracellular matrix

Figure 2

Schematic presentation of the stages of cutaneous wound repair in humans. (A) Immediately after skin injury, the wounded area is filled with a blood clot consisting of blood elements/proteins and vasoactive amines from locally impaired blood vessels within the dermis. Coagulation occurs as platelets aggregate with fibrin. Platelets secret factors such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-β1 that increase vascular permeability and attract neutrophils to the wound site, signalling the early phase of inflammation. Nerve endings are damaged and partially removed by phagocytic keratinocytes. (B) At 24–48 h after injury, neutrophils have undergone apoptosis, while macrophages become the principal inflammatory cell in the wounded area. Endothelial cells infiltrate into the transitioning clot and proliferate to form new blood vessels. Hyper-innervation occurs at the wound. Fibroblasts also migrate into the wounded area and proliferate to deposit a provisional extracellular matrix consisting of new tissue termed granulation tissue. Keratinocytes migrate down the injured dermis above the provisional matrix and begin to proliferate. (C) By 3–10 days after injury, the wound is filled with granulation tissue, and fibroblasts are recruited to the wound by growth factors from macrophages. Fibroblasts then trans-differentiate into myofibroblasts, leading to wound contraction and immature collagen deposition. At this phase, the apical wound portion is overlaid with a neo-epidermis. (D) During remodelling, the rate of collagen synthesis is reduced approximately 2 weeks post-injury. Collagen cross-linking and reorganization can occur for months/years after injury to restore tissue architecture and function. In scar tissue, collagen alignment occurs in a single direction. Tensile strength of (scar) tissue increases over time, but never to that of the pre-injury level

Figure 3

Overview of estrogen, androgen and retinoid nuclear hormone receptor signalling during the phases of cutaneous wound repair. (A) Estrogen sex hormone nuclear receptor (ER) signalling. (B) Androgen nuclear receptor (AR) signalling. For clarification, AR activates immune responses that impair cutaneous wound repair processes. (C) Retinoid acid (RAR) and X receptor (RXR) signalling. See text for references. (+) represents activation, while (‒) represents inhibition. Precise outcomes are explained in the text. Abbreviations: del, deletion; KC, keratinocytes; MMIF, macrophage migration inhibitory factor; MMPs, metalloproteinases; PAS, plasminogen activator system; TGF, transforming growth factor; sol. (soluble)

Figure 4

Overview of vitamin D, peroxisome proliferator-activated and glucocorticoid nuclear hormone receptor signalling during the phases of cutaneous wound repair. (A) Vitamin D receptor (VDR) signalling. (B) Peroxisome proliferator-activated receptor (PPAR) signalling. (C) Glucocorticoid receptor (GR) signalling. See text for references. (+) represents activation, while (–) represents inhibition. Precise outcomes are explained in the text. Abbreviations: 11β-HSD1, 11β-hydroxysteroid dehydrogenase 1; AQP3, aquaporin 3; ECM, extracellular matrix; H₂0₂, hydrogen peroxide; IL, interleukin; TGF, transforming growth factor; TNF, tumour necrosis factor