A protective role of Mer receptor tyrosine kinase in nephrotoxic serum-induced nephritis

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, characterized by a spectrum of autoantibodies that target multiple cellular components. Glomerulonephritis is a major cause of morbidity in patients with SLE. Little is known about the pathogenesis of SLE renal damage and compromised renal function. Activation of both Stat1 and Stat3 has been reported in lupus and lupus nephritis. The reciprocal activation of these two transcription factors may have a major impact on renal inflammation. To study the role of Stat1 in a lupus model, we induced lupus-like chronic graft-versus-host disease (cGVHD) in Stat1-KO and in WT mice by intraperitoneal injection of class II-disparate bm12 splenocytes. WT recipients of these alloreactive cells developed anti-dsDNA autoantibodies starting at week 2 as expected, with a decline after week 4. In contrast, Stat1-KO hosts exhibited a prolonged and significant increase of anti-dsDNA autoantibody responses compared to WT mice (week 4 to week 8). Increased autoantibody titers were accompanied by increased proteinuria and mortality in the cGVHD host mice lacking Stat1. Further analysis revealed expression and activation of Stat3 in the glomeruli of Stat1-KO host mice but not WT mice with cGVHD. Glomerular Stat3 activity in the Stat1-KO mice was associated with increased IL-6 and IFN-γ secretion and macrophage infiltration. Interactions between Stat1 and Stat3 thus appear to be crucial in determining the severity of lupus-like disease in the cGVHD model.

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“…The C T of each test message was first normalized using the C T for GAPDH, assayed in the same sample. Fold change was then calculated (19). …”

Section: Methodsmentioning

confidence: 99%

Stat1 Regulates Lupus-like Chronic Graft-versus-Host Disease Severity via Interactions with Stat3

Shao

Gamero

Zhen

et al. 2015

The Journal of Immunology

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“…Our previous work showed that there is accelerated and more severe NTS-nephritis in the absence of Mer (5). We now show that Axl-KO mice, in contrast, develop reduced renal inflammation with significantly improved survival rate and reduced blood urea nitrogen (BUN), as compared to NTS-treated WT, Mer-KO, and Axl/Mer-double knockout (A/M-KO) mice.…”

Section: Introductionmentioning

confidence: 96%

“…Mice lacking Mer single or TAM triple receptors developed mild or severe lupus-like autoimmune disorders, respectively (14, 15). Mer is highly expressed in glomeruli and functions in the suppression of inflammatory responses and in the clearance of apoptotic cells (5, 14). Mer-KO mice respond to inflammatory stimuli by producing increased proinflammatory mediators such as IL-1, IL-6, and TNFα (5, 20, 21).…”

Section: Introductionmentioning

confidence: 99%

“…Mer is highly expressed in glomeruli and functions in the suppression of inflammatory responses and in the clearance of apoptotic cells (5, 14). Mer-KO mice respond to inflammatory stimuli by producing increased proinflammatory mediators such as IL-1, IL-6, and TNFα (5, 20, 21). Axl, on the other hand, mediates cell survival signaling in many cell types.…”

Section: Introductionmentioning

confidence: 99%

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Opposing Roles of Tyrosine Kinase Receptors Mer and Axl Determine Clinical Outcomes in Experimental Immune-Mediated Nephritis

Zhen

Priest

Shao

2016

The Journal of Immunology

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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.

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“…Activation of Mer, in contrast to Axl, inhibits glomerular inflammation during glomerulonephritis. 65 In antigen-presenting cells, TAM receptor signaling inhibits lipopolysaccharide (LPS)-induced cytokine production (eg, tumor necrosis factor-a [TNF-a]).…”

Section: Tam Receptorsmentioning

confidence: 99%

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Meer

Poll

Veer

2014

Blood

283

228

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TAM receptors (Tyro3, Axl, and Mer) belong to a family of receptor tyrosine kinases that have important effects on hemostasis and inflammation. Also, they affect cell proliferation, survival, adhesion, and migration. TAM receptors can be activated by the vitamin K–dependent proteins Gas6 and protein S. Protein S is more commonly known as an important cofactor for protein C as well as a direct inhibitor of multiple coagulation factors. To our knowledge, the functions of Gas6 are limited to TAM receptor activation. When activated, the TAM receptors have effects on primary hemostasis and coagulation and display an anti-inflammatory or a proinflammatory effect, depending on cell type. To comprehend the effects that the TAM receptors and their ligands have on hemostasis and inflammation, we compare studies that report the different phenotypes displayed by mice with deficiencies in the genes of this receptor family and its ligands (protein S+/−, Gas6−/−, TAM−/−, and variations of these). In this manner, we aim to display which features are attributable to the different ligands. Because of the effects TAM receptors have on hemostasis, inflammation, and cancer growth, their modulation could make interesting therapeutic targets in thromboembolic disease, atherosclerosis, sepsis, autoimmune disease, and cancer.

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A protective role of Mer receptor tyrosine kinase in nephrotoxic serum-induced nephritis

Cited by 29 publications

References 35 publications

Stat1 Regulates Lupus-like Chronic Graft-versus-Host Disease Severity via Interactions with Stat3

Stat1 Regulates Lupus-like Chronic Graft-versus-Host Disease Severity via Interactions with Stat3

Opposing Roles of Tyrosine Kinase Receptors Mer and Axl Determine Clinical Outcomes in Experimental Immune-Mediated Nephritis

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

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