Lupus serum induces skin inflammation through TNFR1 pathway (93.1)

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by high levels of autoantibody and multi-organ tissue damage including kidney and skin. Skin manifestations are frequent in patients with SLE and because of limited understanding of the involved pathogenic mechanisms there is no specific treatment. Skin injury is also frequent in the lupus-prone MRL/lpr mice. We investigated whether lupus serum containing high levels of immunoglobulin can cause skin injury. We found that serum from patients and mice with lupus induced skin inflammation following intradermal injection in normal mice. Immunohistochemistry demonstrated that tumor necrosis factor receptor (TNFR) 1 but not TNFR2 was expressed in the skin lesions caused by injected lupus serum. The expression of NF-kB, iNOS and MCP-1 were also markedly increased in the induced skin lesions. The severity and incidence of lupus serum-induced skin inflammation were significantly decreased in TNF-alpha-deficient mice. Skin inflammation induced by lupus serum was abrogated in TNFR1-deficient mice. In contrast TNFR2 or IL-1R-deficient mice developed skin lesions comparable to those observed in normal mice injected with the same lupus sera. Our studies demonstrate that lupus serum causes skin injury and TNFR1 exerts a crucial role in the pathogenesis of lupus serum-induced skin injury by engaging TNFR1 but not TNFR2 or IL-1R. Therefore, disruption of TNFR1-mediated signaling process may be of therapeutic value in patients suffering of skin in SLE.