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.

Public Health Relevance

Mer and Axl belong to the TAM receptor tyrosine kinase family and play an important role in the clearance of apoptotic cells while aiding in homeostatic immune tolerance. Much attention has been drawn to the immune effector function of the receptors. Mer expression is high in the kidney, and Axl expression i enhanced during kidney inflammation. Antibody-mediated experimental nephritis is a good animal model to uncover the cellular and molecular roles of these receptors in acute immune-induced inflammation. Lupus-prone B6.sle123 mice provide a spontaneous model to study the roles of these receptors in systemic lupus. We have shown that, compared to normal mice, mice lacking Mer have increased renal damage and a lower survival rate when given sheep anti-mouse glomerular basement (anti-GBM) membrane antibody. Axl, in contrast, has been reported to promote the disease through its ligand, Gas6. We will explore the mechanism of Mer and Axl in the anti-GBM model of renal injury and in the spontaneous lupus nephritis mice. The expression pattern of Mer/Axl in the glomerulus and their role in the development of glomerulonephritis may reflect its known functions in regulating cytokine production and facilitating phagocytosis of cellular debris, but may also indicate new functions for these receptors. Further insights into the significance of Mer and it sister receptors not only will enhance our knowledge of inflammatory disease, but may also provide targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK095067-02
Application #
8730143
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2012-12-01
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$129,697
Indirect Cost
$9,607
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Shao, Wen-Hai; Zhen, Yuxuan; Finkelman, Fred D et al. (2014) The Mertk receptor tyrosine kinase promotes T-B interaction stimulated by IgD B-cell receptor cross-linking. J Autoimmun 53:78-84
Shao, Wen-Hai; Cohen, Philip L (2014) The role of tyrosine kinases in systemic lupus erythematosus and their potential as therapeutic targets. Expert Rev Clin Immunol 10:573-82