Psoriatic arthritis under the influence of IFNγ

Abstract

Psoriasis is a common multifactorial autoimmune disease of the skin, and in a large percentage of patients, immune responses involve nail and joint pathology, which develop psoriatic arthritis (PsA). Historically, T helper 1 (Th1)-derived-IFN-γ was abundantly detected in psoriatic skin and its correlation with development and severity of PsO, led to an early classification of psoriasis as a Th1-mediated disease. Investigations of the cellular and molecular mechanisms of PsO pathogenesis in recent years, together with impressive results of biologics against interleukin 17A (IL-17) have shifted focus on IL-17A. However, the contributions of IFN-γ in IL-17 induced pathology and its involvement in the development of PsA have been largely overshadowed. This review summarizes the current knowledge on IFN-γ and provides new insights on the contribution of IFN-γ to PsO and PsA disease pathogenesis and development.

Keywords: IFN-γ; IL-17A; Keratinocyte; Osteoclast; Psoriasis; Psoriatic arthritis.

Figure 1. IFN-γ and IL-17 signaling pathways working together, separately.

Upon binding of IFN-γ, IFN-γ receptor–associated (IFNGR-associated) JAKs phosphorylate STAT1, leading to the formation of STAT1 homodimers. STAT dimers translocate to the cell nucleus and activate gene expression by binding to another class of IFN response elements, the GAS. Upon binding of IL-17A, heteromeric IL-17RA and IL-17RC recruit TRAF6, TRAF2 and TRAF5 via Act1. Activation of TRAF6 results in the triggering of NF-κB, C/EBPβ, and MAPK pathways. TRAF2 and TRAF5 transduce the IL-17 signals to stabilize mRNA transcripts of chemokines and cytokines. TRAF: TNF receptor associated factor, IKK: inhibitor of kappa B kinase.

Figure 2. Cellular mechanisms of IFN-γ function and functional outcomes in PsO and PsA pathophysiology.

Schematic representation depicting IFN-γ expression by multiple cell types including T helper 1 cells (TH1), T helper 17 (Th17), CD8⁺ T cells, γδT and NK/NKT, cells, the target cells of IFN-γ including dendritic cells, macrophages, NK/NKT and mast cells, keratinocytes and osteoclast precursors. Functional outcomes likely to influence the pathophysiology of PsO and PsA by the interaction of IFN-γ producing and responding cells are also depicted including release of cytokines and chemokines to increase Th17 recruitment and differentiation, aberrant hyperproliferation of keratinocytes and terminal differentiation of osteoclasts likely to promote and/or inhibit skin and joint inflammation.