Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b+ conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-α or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC-TLR7 expression for kidney pathogenesis in a murine model of SLE.TLR7 | dendritic cells | SLE | nephritis | autoimmunity

ObjectiveToll‐like receptors (TLRs) 7 and 9 are important innate signaling molecules with opposing roles in the development and progression of systemic lupus erythematosus (SLE). While multiple studies support the notion of a dependency on TLR‐7 for disease development, genetic ablation of TLR‐9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. This study was undertaken to examine the suppressive role of TLR‐9 in the development of severe lupus in a mouse model.MethodsWe crossed Sle1 lupus‐prone mice with TLR‐9–deficient mice to generate Sle1 TLR‐9−/− mice. Mice ages 4.5–6.5 months were evaluated for severe autoimmunity by assessing splenomegaly, GN, immune cell populations, autoantibody and total Ig profiles, kidney dendritic cell (DC) function, and TLR‐7 protein expression. Mice ages 8–10 weeks were used for functional B cell studies, Ig profiling, and determination of TLR‐7 expression.Results Sle1 TLR‐9−/− mice developed severe disease similar to TLR‐9–deficient MRL and Nba2 models. Sle1 TLR‐9−/− mouse B cells produced more class‐switched antibodies, and the autoantibody repertoire was skewed toward RNA‐containing antigens. GN in these mice was associated with DC infiltration, and purified Sle1 TLR‐9−/− mouse renal DCs were more efficient at TLR‐7–dependent antigen presentation and expressed higher levels of TLR‐7 protein. Importantly, this increase in TLR‐7 expression occurred prior to disease development, indicating a role in the initiation stages of tissue destruction.ConclusionThe increase in TLR‐7–reactive immune complexes, and the concomitant enhanced expression of their receptor, promotes inflammation and disease in Sle1 TLR9−/− mice.