Impaired Notch‐MKP‐1 signalling in hidradenitis suppurativa: an approach to pathogenesis by evidence from translational biology

Abstract

Recent findings in familial hidradenitis suppurativa (HS) demonstrated loss-of-function mutations of components of the c-secretase (GS) complex leading to decreased protease cleaving

Hidradenitis Suppurativa Associated with Down Syndrome Is Characterized by Early Age at Diagnosis

“…The underlying molecular mechanisms explaining the association of HS with DS are still not completely known. Evidence suggests that the increased expression of amyloid precursor protein, encoded by a gene located on chromosome 21, might enhance keratinocyte activity, leading to impaired Notch signaling and the development of cutaneous lesions resembling HS [11, 17, 18]. …”

Hidradenitis suppurativa: from pathogenesis to diagnosis and treatment

“…Melnik and Plewig recently proposed the concept of HS as an auto-inflammatory disease characterized by dysregulation of the gamma-secretase/Notch pathway 31,32. Appropriate Notch signaling is of pivotal importance for maintaining the inner and outer root sheath of the hair follicle and skin appendages.…”

Medical and Surgical Treatment of Hidradenitis Suppurativa: A Review

“…Appropriate notch signaling is of pivotal importance for maintaining the inner and outer root sheath of the hair follicle and skin appendages [37,38,39]. Indeed, Melnik and Plewig eloquently described the concept of HS as an autoinflammatory disease with dysregulation of the γ-secretase/notch pathway [40]. Particularly, mutations of the γ-secretase-notch pathway have already been shown to be involved in the molecular pathogenesis of familial HS among Chinese, British, Japanese, and French families [30,31].…”

“…Moreover, deficient notch signaling is able to switch the fate of outer root sheath cells, resulting in the conversion of hair follicles to keratin-enriched epidermal cysts, and compromise apocrine gland homoeostasis also leading to stimulation of toll-like receptor (TLR)-mediated innate immunity by damage-associated molecular pattern molecules released by either ruptured epidermal cysts exposing keratin fibers or altered structural components of less maintained apocrine glands, supporting and maintaining chronic inflammation. Particularly, it is believed that stimulation of TLRs on macrophages and dendritic cells (DCs), the most abundant cells in HS lesions, leads to increased amounts of proinflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1β) and activation of DCs, which secrete IL-23 promoting Th17 cell polarization (IL-17-producing T helper cells were found to infiltrate the dermis in chronic HS lesions) [40,41,42,43,44,45,46]. Due to deficient notch signaling, impaired notch-mediated feedback inhibition of innate immunity by reduced activation of MAPK phosphatase-1 may result in chronic inflammation and Th17-driven auto-inflammation leading to progressive tissue destruction and IL-17-mediated neutrophil attraction in HS [40,41].…”

“…Particularly, it is believed that stimulation of TLRs on macrophages and dendritic cells (DCs), the most abundant cells in HS lesions, leads to increased amounts of proinflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1β) and activation of DCs, which secrete IL-23 promoting Th17 cell polarization (IL-17-producing T helper cells were found to infiltrate the dermis in chronic HS lesions) [40,41,42,43,44,45,46]. Due to deficient notch signaling, impaired notch-mediated feedback inhibition of innate immunity by reduced activation of MAPK phosphatase-1 may result in chronic inflammation and Th17-driven auto-inflammation leading to progressive tissue destruction and IL-17-mediated neutrophil attraction in HS [40,41]. Therefore, as shown above, deficient notch signaling seems to be implicated in the genesis of established HS lesions and their peculiar features (follicular plugging, follicular cysts, reduced volume of sebaceous glands, sinus tracts lined by a stratified epithelium, and neutrophilic abscesses) [47].…”