Transcription Factor Retinoid-Related Orphan Receptor γt: A Promising Target for the Treatment of Psoriasis

Abstract

Psoriasis, which is a common chronic inflammatory skin disease, endangers human health and brings about a major economic burden worldwide. To date, treatments for psoriasis remain unsatisfied because of their clinical limitations and various side effects. Thus, developing a safer and more effective therapy for psoriasis is compelling. Previous studies have explicitly shown that psoriasis is an autoimmune disease that is predominantly mediated by T helper 17 (Th17) cells, which express high levels of interleukin-17 (IL-17) in response to interleukin-23 (IL-23). The discovery of the IL-23-Th17-IL-17 axis in the development of psoriasis has led to the paradigm shift of understanding pathogenesis of psoriasis. Although anti-IL-17 antibodies show marked clinical efficacy in treating psoriasis, compared with antibodies targeting IL-17A or IL-17R alone, targeting Th17 cells themselves may have a maximal benefit by affecting multiple proinflammatory cytokines, including IL-17A, IL-17F, IL-22, and granulocyte-macrophage colony-stimulating factor, which likely act synergistically to drive skin inflammation in psoriasis. In this review, we mainly focus on the critical role of Th17 cells in the pathogenesis of psoriasis. Especially, we explore the small molecules that target retinoid-related orphan receptor γt (RORγt), a vital transcription factor for Th17 cells. Given that RORγt is the lineage-defining transcription factor for Th17 cell differentiation, targeting RORγt via small molecular inverse agonists may be a promising strategy for the treatment of Th17-mediated psoriasis.

Keywords: T helper 17 cells; autoimmune disorder; psoriasis; retinoid-related orphan receptor γt inverse agonist; retinoid-related orphan receptor γt nuclear receptor.

Figure 1

Pathogenesis of psoriasis. Upon activation, keratinocytes secrete LL-37 that in turn activates dendritic cells, which then produce IL-23 and IL-12. IL-23 induces differentiation of naive T cells into Th17 cells that then overproduce IL-17 and IL-22. IL-17 activates keratinocytes, promotes epidermal hyperplasia and recruits proinflammatory cells, resulting in a positive proinflammatory feedback that accelerates the development of psoriasis. Moreover, IL-12 produced by dendritic cells also promotes the differentiation of Th1 cells that in turn produce Th1 cytokines, including IFN-γ. Abbreviations: IL, interleukin; TNF, tumor necrosis factor; IFN-γ, interferon-γ; Th17, T helper 17; IL-23, interleukin-23; IL-17, interleukin-17.

Figure 2

Interplays of interleukin-23 (IL-23), IL-6, signal transducer and activator of transcription 3 (STAT3), and retinoid-related orphan receptor γt (RORγt) in the differentiation of pathogenic T helper 17 (Th17) cells. IL-23 and IL-6 signals activate the JAK–STAT signaling pathway, inducing a strong phosphorylation and dimerization of STAT3. STAT3 homodimers induce the expression and nuclear translocation of RORγt, which in turn promotes Th17 responses by activating Th17 gene promoters, including Il17a, Il17f, Il22, Il26, Il23r, Csf-2, Ccr6, and Ccl20. In addition, IL-23 signaling-induced transcription factor Blimp-1 enhances pathogenic Th17 function by co-localizes RORγt and STAT-3 at Il17a, Il23r, and Csf-2 enhancer sites.