Targeting dendritic cell-specific TNFR2 improves skin and joint inflammation by inhibiting IL-12/ IFN-γ pathways in a mouse model of psoriatic arthritis.

Abstract

Psoriasis (PsO) and Psoriatic arthritis (PsA) are immune-mediated inflammatory diseases affecting the skin and joints. Approximately, 30% of patients with PsO develop PsA over time with both conditions being associated with elevated tumor necrosis factor-alpha (TNF-) expression. TNF- mediates its effect through two membrane receptors, TNFR1 and TNFR2. While current TNF--neutralizing agents, targeting both TNFR1 and TNFR2 receptors, constitute the primary treatment for psoriatic diseases, their long-term use is limited due to an increase in opportunistic infections, tuberculosis reactivation and malignancies likely attributed to TNFR1 inactivation. Recent findings suggest a pivotal role of TNFR2 in psoriatic disease, as evidenced by its amelioration in global TNFR2-knockout (TNFR2KO) mice, but not in TNFR1KO mice. The diminished disease phenotype in TNFR2KO mice is accompanied by a decrease in DC populations. However, the specific contribution of TNFR2 in dendritic cells (DCs) remains unclear. Here, utilizing a mannan-oligosaccharide (MOS)-induced PsA model, we demonstrate a significant reduction in PsA-like skin scaling and joint inflammation in dendritic cell-specific TNFR2 knockout mice (DC-TNFR2KO). Notably, MOS treatment in control mice (TNFR2 fl/fl) led to an increase in conventional type 1 dendritic cells (cDC1) population in the spleen, a response inhibited in DC-TNFR2KO mice. Furthermore, DC-TNFR2KO mice exhibited reduced levels of interleukin-12 (IL-12), a Th1 cell activator, as well as diminished Th1 cells, and interferon-gamma (IFN-{gamma}) levels in the serum compared to controls following MOS stimulation. In summary, our study provides compelling evidence supporting the role of TNFR2 in promoting PsA-like inflammation through cDC1/Th1 activation pathways.