A critical role of TAM receptors in autoimmune nephritis

University Of Cincinnati, Cincinnati OH

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Abstract

DESCRIPTION (provided by applicant: Mer belongs to the TAM subfamily (Tyro-3, Axl, Mer) of receptor tyrosine kinases. Receptors of this family play an important role in apoptotic cell clearance and immune tolerance while performing homeostatic phagocytosis. Nephrotoxic serum (NTS)-induced experimental nephritis has been a useful model that produces pathological changes similar to those seen in immune-mediated glomerulonephritis. Using this model, we found an important protective role for Mer. We showed that Mer-KO mice developed severe early stage renal damage, which led to lower survival. In seeming contrast to these results, Axl was reported to promote mesangial cell proliferation in a similar model, and might hence worsen the disease. In this proposal, we will explore more deeply the physiological functions of both Mer and Axl in the development of experimental nephritis and spontaneous lupus nephritis. Using mice lacking Axl, Mer, or both receptors, we will follow disease development by enumerating apoptotic cells, and by quantitating cytokine/chemokine secretion and leukocyte infiltration and activation. The expression pattern of Mer will be further studied along with Axl in renal cells by FACS and immunofluorescence while following disease progress in those animal models. We will test our hypothesis that the absence of Mer and Axl leads to impaired apoptotic cell clearance and skewed pro-inflammatory cytokine/chemokine secretion and enhanced monocyte/macrophage infiltration in the kidney. Monocytes/macrophages and glomerular cells lacking TAM (Mer-KO, Axl- KO, or Mer/Axl-dKO) receptors are aberrantly activated and severe nephritis occurs. We will construct chimeric mice to ask if the renal damage is caused by resident renal cells or by migrated Mer/Axl- bearing cells. We will further investigate the role of TAM receptors on disease progress in lupus- prone B6/sle123 mice. Results from this study will extend our understanding of the mechanisms in which Mer and Axl regulate chronic inflammation and autoimmunity. Data may reveal potential therapeutic targets for lupus nephritis.