IL-33/Vitamin D Crosstalk in Psoriasis-Associated Osteoporosis

Abstract

Patients with psoriasis (Pso) and, in particular, psoriatic arthritis (PsoA) have an increased risk of developing osteoporosis (OP). It has been shown that OP is among the more common pathologies associated with Pso, mainly due to the well-known osteopenizing conditions coexisting in these patients. Pso and OP share common risk factors, such as vitamin D deficiency and chronic inflammation. Interestingly, the interleukin (IL)-33/ST2 axis, together with vitamin D, is closely related to both Pso and OP. Vitamin D and the IL-33/ST2 signaling pathways are closely involved in bone remodeling, as well as in skin barrier pathophysiology. The production of anti-osteoclastogenic cytokines, e.g., IL-4 and IL-10, is promoted by IL-33 and vitamin D, which are stimulators of both regulatory and Th2 cells. IL-33, together with other Th2 cytokines, shifts osteoclast precursor differentiation towards macrophage and dendritic cells and inhibits receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis by regulating the expression of anti-osteoclastic genes. However, while the vitamin D protective functions in OP and Pso have been definitively ascertained, the overall effect of IL-33 on bone and skin homeostasis, because of its pleiotropic action, is still controversial. Emerging evidence suggests a functional link between vitamin D and the IL-33/ST2 axis, which acts through hormonal influences and immune-mediated effects, as well as cellular and metabolic functions. Based on the actions of vitamin D and IL-33 in Pso and OP, here, we hypothesize the role of their crosstalk in the pathogenesis of both these pathologies.

Keywords: IL-33; bone; cytokines; osteoimmunology; osteoporosis; psoriasis; skin; vitamin D.

Figure 1

Vitamin D deficiency and increased IL-33/ST2 expression in Pso-associated OP. IL-33 could exert contrasting roles in Pso and OP: it might drive the inflammation underlying Pso by inducing the production of dysfunctional keratinocytes and inflammatory cells but could exert protective effects in OP (dashed arrow). Vitamin D, in synergy with IL-33, regulates bone metabolism through PTH release and function, but also increases the soluble decoy receptor sST2 production, thus regulating IL-33 function. The direct action of vitamin D in inhibiting IL-33 function on bone cells is, however, less important than other vitamin D-mediated osteoprotective mechanisms (e.g., the vitamin D capacity to both inhibit Th1 and Th17 inflammation and induce bone protective Th2-type responses). In Pso-associated OP the complex interaction between vitamin D deficiency and increased IL-33/ST2 expression therefore leads to osteoclastogenesis and bone resorption through several mechanisms: PTH hyperproduction, impaired Treg function, increased Th1 and Th17 inflammatory and osteoclastogenic cytokine production, and decreased sST2 expression by lymphocytes and epithelial cells, resulting in an increase in IL-33 induced skin inflammation. Furthermore, the increase in IL-33 in psoriatic patients leads to an increased production of IL-31 which contributes to the worsening of bone loss.