Cross Talk between Proliferative, Angiogenic, and Cellular Mechanisms Orchestred by HIF-1α in Psoriasis

Figure 1

Hypotetical interaction between the keratinocyte and cells from immunologycal system and role of HIF-1α, in the generation of a psoriatic lesions. The following mechanism of epidermal response proposed occurs in healthy individuals. But, in psoriatic patients, this mechanism could generate psoriatic lession, because they might have impaired genes involved in the immune homeostasis (pink zone corresponds to psoriatic skin). When virus, bacteria or a fisical factor interacts with epithelial cells, (a) NFκB is activated via TLR (b) and translocated to nucleus to induce LL-37 and HIF-1α expression. The released LL-37, together with DNA or RNA (c), activates plasmacytoid dendritic cells to produce IFNα and induce the activation of Th17 via IFNγ (d). On the other hand, intracellular LL-37 favors proliferation of keratinocytes inducing IAP-2 expression (e); besides, intracellular LL-37 also facilitates angiogenesis inhibiting the proteosomal degradation of HIF-1α (f) driven by E3/VHL (g) which is downregulated by HDAC-1 (h). After HIF-1α is stabilized by LL-37, HIF-1α is translocated to the nucleous to induce VEGF expression, that is, a potent angiogenic factor (i). The concentrations of VEGF also augment in a feedback manner with IL-13/IL-13R system in keratinocytes (j and k). The released LL-37 is also considered as an alarmin that is able to induce IL-36 production (l) which in turn activates dendritic cells and induce IL-23 production (m). The dendritic cells activate γδ-T cells and ILC (both RORγt⁺) located in the healthy dermal epithelium to trigger the production of IL-17 through PI3/mTOR-HIF-1α-RORγt (n, o, and p). The reclusion of Th17 cells is facilitated by the angiogenesis and chemiotatactic molecules in the psoriatic lession (q) and also Th17 could derive from Treg with nonfuntional CD18 (r and s) to produce even more IL-17 (p) via IL-6-Stat3-HIF-1α-RORγt (t, u, and p) in an activated glycolisys (v). IL-17 induces keratinocytes proliferation (w). Some targets proposed for the treatment for psoriasis are shown. The use of miR-210 (x), the use of STAT3 inhibitors: SOCS3 and Sta-21, (y) the downexpression of VHL (g), and the high expression of IL-13Rα (z).