title: Opposing Roles of Tyrosine Kinase Receptors Mer and Axl Determine Clinical Outcomes in Experimental Immune-Mediated Nephritis.
abstract: Glomerulonephritis is one of the most severe manifestations of systemic lupus erythematosus, with considerable morbidity and mortality. There remains a major unmet need for successful management of lupus nephritis. TAM family receptor tyrosine kinases (Mer and Axl) play an important role in the maintenance of immune homeostasis in the kidney. Mer is constitutively expressed in the glomeruli; Axl expression is inducible in glomeruli under inflammatory conditions. To investigate the distinct functions of Axl and Mer in lupus nephritis, we compared the severity of nephrotoxic serum glomerulonephritis in wild-type (WT), Axl-knockout (KO), Mer-KO, and Axl/Mer-KO mice. Mer-KO mice developed severe glomerulonephritis, with significantly decreased survival and increased blood urea nitrogen levels compared with WT mice given the same treatment. However, nephrotoxic serum-treated Axl-KO mice had significantly increased survival rates and improved renal function compared with similarly treated WT, Mer-KO, and Axl/Mer-KO mice. Interestingly, mice lacking both Axl and Mer developed kidney inflammation comparable to WT mice. Western blot analysis revealed significantly increased Stat3 phosphorylation and caspase-1 activation in the kidneys of nephritic Mer-KO mice. In contrast, Axl-deficient nephrotoxic serum-injected mice showed decreased Akt phosphorylation and Bcl-xL upregulation. Thus, the reciprocal activation of Axl and Mer receptor tyrosine kinases has a major impact on the outcome of renal inflammation.
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Stephen O
authors.identifier: 0000-0001-5486-809X
authors.initials: SO
authors.lastname: Priest
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140 shaowi@ucmail.uc.edu.
authors.forename: Wen-Hai
authors.identifier: 0000-0002-4397-0539
authors.initials: WH
authors.lastname: Shao
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000502:physiology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology; D008181:Lupus Nephritis / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000037:antagonists & inhibitors; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D020170:Caspase 1; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; C490767:Mertk protein, mouse; C000722290:AXL receptor tyrosine kinase, mouse