Molecular mechanisms of postinflammatory hyperpigmentation

Abstract Postinflammatory hyperpigmentation (PIH) disorder is a condition in which pigmentation is abnormally increased (hypermelanosis) in skin areas that are affected by cutaneous inflammation or injury. PIH can arise in individuals of all skin types, but particularly and most frequently affects individuals with skin of color with Fitzpatrick type III and higher skin types, including Africans, African Americans, Hispanics/Latinos, Asians, Native Americans, Pacific Islanders, and those of Middle Eastern descent. In fact, PIH is the most common pigmentary disorder in patients with skin of color. PIH can have devastating psychological and quality-of-life-associated effects on the patients. Despite being so common, PIH remains severely understudied and its molecular mechanisms remain largely elusive. PIH is a response of skin to cutaneous inflammatory stimulations such as allergic contact dermatitis, acne and skin wounding. At the inflamed and wounded sites, the hyperpigmentation is due to an increased production and secretion of melanin pigment by melanocytes and can last for months to years, or even permanently. The current treatment options have limited efficacy, and can have undesirable side effects upon usage for longer periods. Consequently, the need for new and safer treatment options remains as dire as ever. Prevention of PIH is considered as the primary and the most valuable option; however, complex unknown pathogenesis of PIH contributes to the current lack of prevention strategies. Skin inflammation process recruits robust cytokine-secreting inflammatory cells that secrete interferon-gamma (IFNG) cytokine into the skin microenvironment, which then orchestrates the inflammatory processes. For example, IFNG plays an important role in wound healing process. Our preliminary studies suggest that IFNG induces melanin synthesis in melanocytic cells. In this proposal, we will study IFNG signaling pathway as a novel instigator of PIH and a viable target for prevention and treatment strategy for PIH. We propose two aims. In Aim 1, we will elucidate the molecular mechanisms of IFNG-mediated melanogenesis, including the role of IFNG-induced hyperglycosylation of Tyrosinase and melanosomal alkalization in inducing melanogenesis. In Aim 2, we will determine whether IFNG mediates PIH using novel in vivo mouse models. We will develop novel mouse models of PIH by utilizing chemically induced inflammation and wound-healing assays using the SKH2/J hairless and ARE-Del-/- (chronic IFNG producing) mice. We will then ask whether genetic ablation of IFNG signaling in melanocytes inhibits PIH. Finally, we will perform proof-of-principle preclinical studies to test whether inhibition of IFNG signaling can block PIH.