Abstract
TNF-α, a proinflammatory cytokine, is a crucial mediator of psoriasis pathogenesis. TNF-α functions by activating TNFR1 and TNFR2. Anti-TNF drugs that neutralize TNF-α, thus blocking the activation of TNFR1 and TNFR2, have been proven highly therapeutic in psoriatic diseases. TNF-α also plays an important role in host defense; thus, anti-TNF therapy can cause potentially serious adverse effects, including opportunistic infections and latent tuberculosis reactivation. These adverse effects are attributed to TNFR1 inactivation. Therefore, understanding the relative contributions of TNFR1 and TNFR2 has clinical implications in mitigating psoriasis versus global TNF-α blockade. We found a significant reduction in psoriasis lesions as measured by epidermal hyperplasia, characteristic gross skin lesion, and IL-23 or IL-17A levels in Tnfr2-knockout but not in Tnfr1-knockout mice in the imiquimod psoriasis model. Furthermore, imiquimod-mediated increase in the myeloid dendritic cells, TNF/inducible nitric oxide synthase‒producing dendritic cells, and IL-23 expression in the draining lymph nodes were dependent on TNFR2 but not on TNFR1. Together, our results support that psoriatic inflammation is not dependent on TNFR1 activity but is driven by a TNFR2-dependent IL-23/IL-17 pathway activation. Thus, targeting the TNFR2 pathway may emerge as a potential next-generation therapeutic approach for psoriatic diseases.