TY - JOUR T1 - Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation JF - Proceedings of the National Academy of Sciences JO - Proc Natl Acad Sci USA DO - 10.1073/pnas.1300617110 SP - 201300617 AU - Lamagna, Chrystelle AU - Scapini, Patrizia AU - van Ziffle, Jessica A. AU - DeFranco, Anthony L. AU - Lowell, Clifford A. Y1 - 2013/08/09 UR - http://www.pnas.org/content/early/2013/08/08/1300617110.abstract N2 - The pathogenesis of systemic lupus erythematosus, a complex autoimmune inflammatory disease triggered by genetic and environmental factors, is generally attributed to defects in lymphocyte function. We show that dendritic cells (DCs) also drive autoimmune disease in mice. Our observations that dysregulation of Toll-like receptor signaling (a key pathway that alerts the immune system of encounter with infectious agents) in DCs alone is sufficient to induce autoimmunity sheds new light on the pathogenesis of this disease. This work implies that DC-specific reduction of Toll-like receptor signaling may prove to be a highly specific approach to reduce the symptoms of autoimmune diseases.Deletion of lyn, a Src-family tyrosine kinase expressed by B, myeloid, and dendritic cells (DCs), triggers lupus-like disease in mice, characterized by autoantibody production and renal immune complex deposition leading to chronic glomerulonephritis. B cells from these mice are hyperactive to antigen-receptor stimulation owing to a loss of inhibitory signaling mediated by Lyn kinase. The hyperactive B-cell responses are thought to underlie the development of autoimmunity in this model. Lyn-deficient mice also manifest significant myeloexpansion. To test the contribution of different immune cell types to the lupus-like disease in this model, we generated a lynflox/flox transgenic mouse strain. To our surprise, when we crossed these mice to Cd11c-cre animals, generating DC-specific deletion of Lyn, the animals developed spontaneous B- and T-cell activation and subsequent production of autoantibodies and severe nephritis. Remarkably, the DC-specific Lyn-deficient mice also developed severe tissue inflammatory disease, which was not present in the global lyn−/− strain. Lyn-deficient DCs were hyperactivated and hyperresponsive to Toll-like receptor agonists and IL-1β. To test whether dysregulation of these signaling pathways in DCs contributed to the inflammatory/autoimmune phenotype, we crossed the lynf/f Cd11c-cre+ mice to myd88f/f animals, generating double-mutant mice lacking both Lyn and the adaptor protein myeloid differentiation factor 88 (MyD88) in DCs, specifically. Deletion of MyD88 in DCs alone completely reversed the inflammatory autoimmunity in the DC-specific Lyn-mutant mice. Thus, we demonstrate that hyperactivation of MyD88-dependent signaling in DCs is sufficient to drive pathogenesis of lupus-like disease, illuminating the fact that dysregulation in innate immune cells alone can lead to autoimmunity. ER -