Targeting dendritic cell-specific TNFR2 improves skin and joint inflammation in a murine model of psoriatic arthritis.

Psoriasis (PsO) and Psoriatic arthritis (PsA) are TNF-alpha-dependent immune-mediated inflammatory diseases where dendritic cells (DC) play a critical role in disease pathogenesis. Although TNF-alpha receptor 2 (TNFR2) has been implicated in the pathology of psoriatic diseases, its specific role in DC mediated responses remains unclear. To investigate the role of TNFR2 in DC in psoriatic disease, we utilized the mannan-oligosaccharide (MOS) model of PsA on mice with either TNFR2 intact or with DC-specific TNFR2 knockout (DC-TNFR2KO). We evaluated disease severity by assessing skin scaling, joint inflammation, serum cytokine profiles, and changes in the conventional type 1 dendritic cell (cDC1) population. A significant reduction in PsA-like skin scaling and joint inflammation was observed in DC-TNFR2KO mice. In control mice, MOS stimulated a robust increase in the cDC1 population, a response that was notably suppressed in the absence of DC-TNFR2. Furthermore, serum levels of key pro-inflammatory cytokines such as interleukin-12 (IL-12), TNF-alpha, IL-23 and IL-17 A were significantly diminished in DC-TNFR2KO mice following MOS exposure. Our findings provide compelling evidence that TNFR2 signaling in DC is instrumental in promoting PsA-like inflammation. These results highlight the potential of targeting the DC-TNFR2-pathways as a novel therapeutic strategy for PsA and related immune-mediated inflammatory diseases.