Neutrophil plasticity in autoimmune disease

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Autoimmune disease is the third most common disease category after cancer and heart disease. Current therapies often rely on broad-spectrum immunosuppressive drugs to reduce inflammation and thus prevent permanent organ damage and chronic disease. Neutrophils are considered short-lived cells with degradative properties that associate with organ damage in diseases ranging from rheumatoid arthritis and Crohn’s to lupus nephritis. Deletion of activating FcγRs, receptors for IgG protects from organ damage in many mouse models of autoimmune diseases and FcγR SNPs are linked to rheumatoid arthritis, lupus and other autoimmune disorders. We have shown that IgG-immune complex deposition within blood vessels triggers rapid neutrophil capture via their own FcγRs and subsequent renal injury in a model of glomerulonephritis, suggesting that neutrophil FcγRs serve as a key link between IgG deposition and organ damage. What is the fate of activated neutrophils? Neutrophils can transdifferentiate into dendritic cells (DC) in response to cytokines in vitro and neutrophils with DC markers (nDC) are observed in inflamed mouse and human tissues. This suggests that the neutrophil imprint may go beyond the acute stages of inflammation. Based on preliminary data in mouse models and lupus patient blood we propose the following. Neutrophil FcγR engagement with multivalent IgG-complexed antigen induces neutrophil transdifferentiation into immunogenic, antigen cross-presenting nDCs that elicit T cell dependent acquired immunity and organ damage, which contributes to the transition from acute to chronic autoimmune disease. This hypothesis will be tested using our humanized FcγR mice, neutrophil reporter mice, mouse models of autoimmune target organ injury and systemic lupus erythematosus (SLE) patient blood coupled with transcriptome profiling, functional assays and multiphoton intravital microscopy. In specific aims, we propose to understand the molecular underpinnings of the FcγR dependent neutrophil to DC transition, the evolution of nDC fate, trafficking and immunogenic profile during the course of IgG mediated inflammation and the role of nDCs in promoting organ damage. Here, we will focus on nephrotoxic nephritis, a model of glomerulonephritis that mimics aspects of the effector phase of lupus nephritis, and T cell mediated tubulointerstitial nephritis, which are leading causes of end stage renal disease, but fully anticipate a broader applicability of our results to other IgG-mediated autoimmune diseases. Successful completion of our aims will lead to the characterization of a unique population of potent antigen presenting cells that develop from neutrophils exposed to autoantibody-ICs and may provide evidence that they establish a feed forward loop that fuels inflammation and thus increases the risk for transition to chronic autoimmune disease. We anticipate that this will lay the groundwork for elucidating novel points for therapeutic intervention in autoimmune disorders.