The Interplay Between Keratinocytes and Immune Cells in the Pathogenesis of Psoriasis

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.

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation

“…To further explore the mechanism for increased γδ T cell numbers in the skin of untreated K14-KO mice, we analyzed the expression of T cell-associated chemokines and their receptors. Skin-infiltrating T cells can express Ccr2, Ccr4, or Ccr6, whereas their corresponding ligands, Ccl2, Ccl20, and Ccl17, are secreted by keratinocytes or endothelial cells (24), thus triggering the recruitment of different lymphocyte subsets into the inflamed skin. Our analyses revealed that in particular Ccl2 and, to a minor extent, Ccl17 and Ccl20 were overexpressed in the skin of untreated IκBζ-deficient K14-KO mice compared with control mice ( Figure 3E).…”

Role of bulge epidermal stem cells and TSLP signaling in psoriasis

“…Interestingly, some arachidonic acid metabolites can regulate the survival of different adult stem cell populations (Widera et al, 2006;Porter et al, 2013). Furthermore, these pro-inflammatory mediators may also be involved in the recruitment of inflammatory cells, such as dendritic cells, neutrophils, or T cells (Albanesi et al, 2018).…”

Negative regulation of dendritic cell activation in psoriasis mediated via CD100–plexin‐B2

“…Interactions among KCs, DCs, and T cells via various cytokines govern the initiation and maintenance of psoriatic inflammation; however, the regulatory mechanisms in both of these phases remain largely unknown. Previous studies indicated that activation of KCs initiates the early phase in response to stress, trauma or infection, and produces innate molecules such as LL37 to activate plasmacytoid DCs and mDCs, which produces IL-36 and IL-23 to induce a T-cell response; the cytokines produced by T cells and DCs induce the proliferation of KCs and production of more pro-inflammatory cytokines and chemokines, constituting a vicious feedback loop [1,11,30,31]. By using the IMQ-induced psoriatic model in CD100 −/− mice, we found that CD100 differentially regulated skin inflammation via DCs and KCs.…”