Abstract
Psoriasis is a chronic inflammatory skin disease resulting from genetic, epigenetic, environmental, and lifestyle factors. To date, several immunopathogenic mechanisms of psoriasis have been elucidated, and, in the current model, the cross talk between autoreactive T cells and resident keratinocytes generates inflammatory and immune circuits responsible for the initiation, progression, and persistence of the disease. Several autoantigens derived from keratinocytes (i.e., LL37 cathelecidin/nucleic acid complexes, newly generated lipid antigens) have been identified, which may trigger initial activation of T cells, particularly IL-17-producing T cells, T helper (Th)1 and Th22 cells. Hence, lymphokines released in skin lesions are pivotal for keratinocyte activation and production of inflammatory molecules, which in turn lead to amplification of the local immune responses. Intrinsic genetic alterations of keratinocytes in the activation of signal transduction pathways dependent on T-cell-derived cytokines are also fundamental. The current review emphasizes the aberrant interplay of immune cells and skin-resident keratinocytes in establishing and sustaining inflammatory and immune responses in psoriasis.
Highlights
Psoriasis is a chronic inflammatory skin disorder involving both innate and adaptive immunity processes
A number of single-nucleotide polymorphisms (SNP) were found in genes encoding molecules involved in IL-17 or TNF-α responses, even though functional studies correlating their presence to keratinocyte susceptibility to these cytokines are lacking and controversial
Allelic variants were found in NFKBIZ, TRAF3IP2, and TNFAIP3 genes [62] encoding IKBζ, Act-1 and the Act1-dependent A20 protein, respectively, all involved in IL-17 molecular signaling [57]
Summary
Psoriasis is a chronic inflammatory skin disorder involving both innate and adaptive immunity processes. Intrinsic or genetic alterations of keratinocytes in the activation of key signaling pathways induced by immune cell-derived cytokines may be responsible for the typical unbalance between proliferation and differentiation processes, as well as inflammatory signatures observed in psoriatic epidermis [14, 15]. Important studies aimed at identifying the initial trigger of psoriasis demonstrated that injured keratinocytes enable pDC-, concomitantly to mDC-driven immune responses through LL37/ nucleic acid complexes, highly released in psoriatic epidermis after skin trauma [11, 17]. These multimeric LL37–nucleic acid complexes induce overproduction of type I IFN by pDC as well as TNF-α and IL-6 by mDC [11, 18]. Other than activating innate immune responses, IL-1α has found to promote keratinocyte and endothelial cell proliferation and activation [31]
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