Kaur Raminderjit, Lin Jean, Harvey Jennifer E, Brambilla Roberta, Chandrasekharan Unnikrishnan M, Husni M Elaine
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, USA.
Sci Rep. 2025 Aug 27;15(1):31574. doi: 10.1038/s41598-025-15175-6.
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.
银屑病（PsO）和银屑病关节炎（PsA）是肿瘤坏死因子-α（TNF-α）依赖性免疫介导的炎症性疾病，其中树突状细胞（DC）在疾病发病机制中起关键作用。尽管TNF-α受体2（TNFR2）与银屑病疾病的病理过程有关，但其在DC介导的反应中的具体作用仍不清楚。为了研究TNFR2在银屑病疾病中DC的作用，我们在TNFR2完整或DC特异性TNFR2基因敲除（DC-TNFR2KO）的小鼠上利用了PsA的甘露寡糖（MOS）模型。我们通过评估皮肤鳞屑、关节炎症、血清细胞因子谱以及传统1型树突状细胞（cDC1）群体的变化来评估疾病严重程度。在DC-TNFR2KO小鼠中观察到PsA样皮肤鳞屑和关节炎症显著减轻。在对照小鼠中，MOS刺激cDC1群体显著增加，而在没有DC-TNFR2的情况下这种反应明显受到抑制。此外，在MOS暴露后，DC-TNFR2KO小鼠血清中关键促炎细胞因子如白细胞介素-12（IL-12）、TNF-α、IL-23和IL-17 A的水平显著降低。我们的研究结果提供了令人信服的证据，表明DC中的TNFR2信号传导有助于促进PsA样炎症。这些结果突出了靶向DC-TNFR2途径作为PsA和相关免疫介导炎症性疾病的新型治疗策略的潜力。
