Abstract
Psoriasis is a common autoimmune and chronic inflammatory skin disorder globally affecting 0.51–11.43% of adults. Inflammation-associated cell death in keratinocytes plays a key role in the process of integrate inflammatory cascade in psoriasis. Necroptosis is a regulated necrotic cell death mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), which participates in many human inflammatory diseases. However, the mechanism and function of programmed necrosis in psoriasis is not well-illustrated. In the current study, we provide evidence for the involvement of necroptosis in psoriasis. RIPK1 and MLKL were significantly upregulated and localized in all layers of the epidermis in human psoriatic lesions, while RIPK3 and phosphorylated MLKL were mainly expressed in keratinocytes, which located in the upper layers. Increased tendency of necroptosis was also found in IMQ-induced psoriasiform skin of mice. Further, we discovered that both the inhibitor of RIPK1 R-7-Cl-O-Necrostatin-1 (Nec-1s) and MLKL-inhibitor necrosulfonamide (NSA) suppressed necroptosis in HaCaT cells and IMQ mouse models, powerfully blocked IMQ-induced inflammatory responses in vivo, and significantly downregulated the production of inflammatory factors like IL-1β, IL-6, IL-17A, IL-23a, CXCL1, and CCL20. These findings promote the development of new therapies for the treatment of necroptosis-activated pathologies for psoriasis.
Highlights
Psoriasis is a common autoimmune and chronic inflammatory skin disorder portrayed as hyperproliferation and maturation impairment of keratinocytes, increased immune cells infiltration and blood vessel formation, and accumulation in proinflammatory cytokines[1]
Increased expression of pRIPK1 and RIPK3 in the epidermis of human psoriasis samples compared to nonlesional skin has been observed by immunohistochemistry[15,19], there is a lack of convincing evidence supporting the activity of necroptosis in human psoriasis
receptor interacting protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like pseudokinase (MLKL), and Phosphorylated MLKL (pMLKL) were expressed in the basal layer of the epidermis in normal skin, whereas in human psoriatic skin lesions, RIPK1 and MLKL were significantly expressed in in all layers of the epidermis peculiarly with the strongest expression of MLKL, while RIPK3 and pMLKL were mainly expressed in the upper layers (Fig. 1a)
Summary
Psoriasis is a common autoimmune and chronic inflammatory skin disorder portrayed as hyperproliferation and maturation impairment of keratinocytes, increased immune cells infiltration and blood vessel formation, and accumulation in proinflammatory cytokines[1]. The prevalence of psoriasis in adults is 0.51–11.43%2. Psoriasis intrinsic defects exacerbate the imbalance between anti-inflammatory and proinflammatory signals in an autocrine or paracrine manner that contributes to various aspects of its pathogenesis[3]. Keratinocytes play a pivotal role in the early stage of psoriasis and in the maintenance of chronic course. A recent study provided compelling evidence that keratinocytes are critical for the development of complete psoriasis inflammatory cascade[4]. Destruction of the epidermal barrier of psoriasis makes keratinocytes more susceptible to various external harmful substances, causing cell damage or even cell death
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