Inhibition of TNFR1 signaling by P60 PLAD protein ameliorates skin lesions in lupus MRL/lpr mice (50.24)

Abstract

Abstract Skin disease is the second most common manifestation in patients with systemic lupus erythematosus (SLE). The etiology of skin injury remains unclear. There is urgent need to understand better the pathogenesis of skin lesions and to develop effective, non-toxic therapy for cutaneous lupus erythematosus. MRL/lpr mice develop pathology similar to human SLE including skin lesions. To understand whether tumor necrosis factor (TNF) contributes to the pathogenesis of cutaneous lupus erythematosus, we treated lupus MRL/lpr mice with TNF receptor (R) defined PLAD protein. P60 PLAD inhibits the function of TNFR1, whereas P80 PLAD inhibits the function of TNFR2. We found that P60 PLAD protein significantly inhibited skin injury but P80 PLAD failed to do so in MRL/lpr mice. Both PLAD proteins promoted the development of proteinuria. Immunohistochemistry studies of skin lesions demonstrated that TNFR1 but not TNFR2 in expressed in the skin lesion of MRL/lpr mice. P60 PLAD significantly inhibited NF-kB, MCP-1 and iNOS expression by skin keratinocytes. Our results indicate that TNFR1 contributes to the development of skin lesions in lupus-prone mice suggest that it can be targeted successfully to treat cutaneous SLE.