Opposing roles of tyrosine kinase receptors Mer and Axl determine clinical outcome in a mouse model of nephritis

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disorder with unknown etiology. Lupus nephritis remains one of the most severe manifestations of SLE, with considerable morbidity and mortality. There remains a major void in the successful management of lupus nephritis. TAM (Tyro-3, Axl and Mer) receptor tyrosine kinases play an important role in the maintenance of immune homeostasis. Mer is constitutively highly expressed on glomerular endothelial cells; Axl expression is inducible in kidney under inflammatory conditions. To investigate the functions of Axl and Mer in lupus nephritis, we induced glomerulonephritis in WT, Axl-KO, Mer-KO, and A/M-KO (Axl/Mer-double knockout) mice by injection of nephrotoxic serum (NTS). Mer-KO mice developed severe glomerulonephritis, with significantly decreased survival rate and increased blood urea nitrogen (BUN) levels as compared to WT mice given the same treatment. Two weeks after injection, necrotic cell death was evident in the glomeruli of Mer-KO mice. However, Axl-KO presented with significantly increased survival rate and reduced BUN as compared to the WT, Mer-KO and A/M-KO mice injected with the same serum. Interestingly, the A/M-KO mice developed kidney inflammation comparable to WT mice. Western blot analysis revealed significantly increased Stat3 phosphorylation and caspase-1 activation in the kidney of Mer-KO mice after NTS injection. In contrast, Axl deficient NTS-injected mice developed decreased Akt phosphorylation and Bcl-xl upregulation. The reciprocal activation of Axl and Mer receptor tyrosine kinases may have a major impact on renal inflammation. Results from these studies may lead to novel therapeutic drug development targeted to lupus nephritis.