Inflammasomes: emerging therapeutic targets in hidradenitis suppurativa?

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterised by recurrent inflammatory lesions, which affect skin and hair follicles in intertriginous areas. HS has a multifactorial aetiology resulting in barrier dysfunction associated with aberrant immune activation. There is increased evidence for the role of inflammasomes in the pathophysiology of inflammatory skin diseases, including HS. Inflammasomes are multiprotein complexes activated following exposure to danger signals including microbial ligands and components of damaged host cells. Inflammasome activation induces many signalling cascades and subsequent cleavage of pro-inflammatory cytokines, most notably interleukin (IL)-1ß, which have a role in HS pathogenesis. Limited immunotherapies are approved for treating moderate-to-severe HS, with variable response rates influenced by disease heterogeneity. Inflammasomes represent attractive targets to suppress multiple inflammatory pathways in HS including IL-1ß and IL-17. This review aims to summarise the role of inflammasomes in HS and to evaluate evidence for inflammasomes as therapeutic targets for HS treatment.

Beyond the Epidermal-Melanin-Unit: The Human Scalp Anagen Hair Bulb Is Home to Multiple Melanocyte Subpopulations of Variable Melanogenic Capacity.

The visual appearance of humans is derived significantly from our skin and hair color. While melanin from epidermal melanocytes protects our skin from the damaging effects of ultraviolet radiation, the biological value of pigmentation in the hair follicle, particularly on the scalp, is less clear. In this study, we explore the heterogeneity of pigment cells in the human scalp anagen hair follicle bulb, a site conventionally viewed to be focused solely on pigment production for transfer to the hair shaft. Using c-KIT/CD117 microbeads, we isolated bulbar c-KIT-positive and c-KIT-negative melanocytes. While both subpopulations expressed MITF, only the c-KIT-positive fraction expressed SOX10. We further localized bulbar melanocyte subpopulations (expressing c-KIT, SOX10, MITF, and DCT) that exhibited distinct/variable expression of downstream differentiation-associated melanosome markers (e.g., gp100 and Melan-A). The localization of a second 'immature' SOX10 negative melanocyte population, which was c-KIT/MITF double-positive, was identified outside of the melanogenic zone in the most peripheral/proximal matrix. This study describes an approach to purifying human scalp anagen hair bulb melanocytes, allowing us to identify unexpected levels of melanocyte heterogeneity. The function of the more immature melanocytes in this part of the hair follicle remains to be elucidated. Could they be in-transit migratory cells ultimately destined to synthesize melanin, or could they contribute to the hair follicle in non-melanogenic ways?

Investigation of the Role of Interleukin 6 in Vitiligo Pathogenesis.

Interleukin-6 (IL6) is involved in pathogenesis of several autoimmune disorders including vitiligo. Hence, we aimed to investigate the association of IL6 -174 G/C and -572 G/C polymorphisms and its transcript levels with vitiligo; to evaluate the effect of IL-6 on normal human melanocyte (NHM) viability and expression of IL6R, MITF and TYR. IL6 -174 G/C and -572 G/C polymorphisms were genotyped by ARMS-PCR and PCR-RFLP respectively in 343 controls and 322 vitiligo patients. IL6 transcript levels were estimated from PBMCs (96 controls and 77 patients) and skin samples (15 controls and 15 patients) by qPCR. NHM viability was assessed by MTT; IL6R, MITF and TYR transcript and protein levels were monitored by qPCR and ICC respectively. Genetic analyses revealed no association of IL6 -174 G/C polymorphism (p> .05) with vitiligo. Analysis of IL6 -572 G/C revealed reduced risk of vitiligo in individuals with GC/CC genotypes compared to GG genotype (p = .010). IL6 expression was significantly increased (p = .0197) in PBMCs of patients. Further, IL6 expression was significantly higher in non-lesional skin compared to controls (p = .009). In-vitro NHM viability was decreased upon IL-6 exposure (10-50 ng/ml; p< .05), with significantly increased IL6R transcript (p = .042) and protein levels (p = .003) however, MITF transcript (p = .0003) and protein levels (p = .016), and TYR transcript levels (p = .001) were significantly decreased. The results suggest that IL6 -572 G/C polymorphism might be associated with vitiligo susceptibility in Gujarat population. Moreover, increased IL6 expression in vitiligo patients and its effect on NHM suggest a potential role in melanocyte biology. CONCLUSION: The results suggest that IL6 - 572 G/C polymorphism might be associated with vitiligo susceptibility in Gujarat population. Moreover, increased IL6 expression in vitiligo patients and its effect on NHM suggest a potential role in melanocyte biology.

Loss of 'Epidermal Melanin Unit' Integrity in Human Skin During Melanoma-Genesis.

Cutaneous melanoma can be a most challenging neoplasm of high lethality, in part due to its extreme heterogeneity and characteristic aggressive and invasive nature. Indeed, its moniker 'the great masquerader' reflects that not all melanomas are created equal in terms of their originating cellular contexts, but also that melanoma cells in the malignant tumor can adopt a wide range of different cell states and variable organotropism. In this review, we focus on the early phases of melanomagenesis by discussing how the originating pigment cell of the melanocyte lineage can be influenced to embark on a wide range of tumor fates with distinctive microanatomical pathways. In particular, we assess how cells of the melanocyte lineage can differ by maturation status (stem cell; melanoblast; transiently amplifying cell; differentiated; post-mitotic; terminally-differentiated) as well as by micro-environmental niche (in the stratum basale of the epidermis; within skin appendages like hair follicle, eccrine gland, etc). We discuss how the above variable contexts may influence the susceptibility of the epidermal-melanin unit (EMU) to become unstable, which may presage cutaneous melanoma development. We also assess how unique features of follicular-melanin unit(s) (FMUs) can, by contrast, protect melanocytes from melanomagenesis. Lastly, we postulate how variable melanocyte fates in vitiligo, albinism, psoriasis, and alopecia areata may provide new insights into immune-/non immune-mediated outcomes for melanocytes in cutaneous melanin units.

A Concise Review on the Role of Endoplasmic Reticulum Stress in the Development of Autoimmunity in Vitiligo Pathogenesis.

Vitiligo is characterized by circumscribed depigmented macules in the skin resulting due to the autoimmune destruction of melanocytes from the epidermis. Both humoral as well as cell-mediated autoimmune responses are involved in melanocyte destruction. Several studies including ours have established that oxidative stress is involved in vitiligo onset, while autoimmunity contributes to the disease progression. However, the underlying mechanism involved in programing the onset and progression of the disease remains a conundrum. Based on several direct and indirect evidences, we suggested that endoplasmic reticulum (ER) stress might act as a connecting link between oxidative stress and autoimmunity in vitiligo pathogenesis. Oxidative stress disrupts cellular redox potential that extends to the ER causing the accumulation of misfolded proteins, which activates the unfolded protein response (UPR). The primary aim of UPR is to resolve the stress and restore cellular homeostasis for cell survival. Growing evidences suggest a vital role of UPR in immune regulation. Moreover, defective UPR has been implicated in the development of autoimmunity in several autoimmune disorders. ER stress-activated UPR plays an essential role in the regulation and maintenance of innate as well as adaptive immunity, and a defective UPR may result in systemic/tissue level/organ-specific autoimmunity. This review emphasizes on understanding the role of ER stress-induced UPR in the development of systemic and tissue level autoimmunity in vitiligo pathogenesis and its therapeutics.