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 WT, Axl-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 to WT mice given the same treatment. However, nephrotoxic serum-treated Axl-KO mice had significantly increased survival rates and improved renal function as compared to 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.

Mechanism of Mer receptor tyrosine kinase inhibition of glomerular endothelial cell inflammation

“…2C and D). Consistent with our previous findings [19], p38MAP kinase remained undetectable in primary GECs regardless of Mer expression (data not shown). Taken together, these data suggest an inhibitory function of Mer in regulating LPS-mediated Akt and ERK1/2 expression and activation.…”

“…Consistent with this, renal Mer expression, which was originally demonstrated by Northern blot [20, 21], is highest in both mice and humans in the kidney [19–21]. We confirmed renal expression of Mer protein by Western blot [19] and by immunofluorescent staining (Fig. 1B).…”

“…We previously reported that Mer protects against renal inflammation [18, 19]. Consistent with this, renal Mer expression, which was originally demonstrated by Northern blot [20, 21], is highest in both mice and humans in the kidney [19–21].…”

“…In addition, Mer-KO mice have been shown to be hypersensitive to LPS [17]. Our previous work showed that Mer down-regulates renal inflammation, with consequent increased susceptibility to anti-glomerular basement membrane (GBM)-mediated kidney damage in Mer-deficient mice [18, 19]. Consistent with this, Mer is highly expressed in the glomerulus and is upregulated upon kidney inflammation [18, 20].…”

Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression

“…In the context of these possibilities, a study showed that advanced human carotid arteries were enriched in MerTK when compared with normal carotid arteries and that Protein S levels increased with advanced plaque grade20. While both Axl and Mertk are considered to be involved in efferocytosis and suppression of inflammation, a recent report raises the possibility that they may play opposing roles in certain inflammatory settings, such as that seen in a mouse model of nephrotoxic serum-induced glomerulonephritis21. Because that study was conducted using holo-Axl KO and holo-Mertk KO, the specific cell types that are responsible for these opposing effects remain to be elucidated.…”