Delayed Apoptotic Cell Clearance and Lupus-like Autoimmunity in Mice Lacking the c-mer Membrane Tyrosine Kinase

By Philip L. Cohen, R. Caricchio, Valsamma Abraham, Todd D. Camenisch, J. Jennette, R. Roubey, H. Earp, G. Matsushima, E. Reap. Journal of Experimental Medicine, 2002

671 citations recorded by the source corpus.

Mice lacking the membrane tyrosine kinase c-mer have been shown to have altered macro-phage cytokine production and defective phagocytosis of apoptotic cells despite normal phagocytosis of other particles. We show here that c-mer–deficient mice have impaired clearance of infused apoptotic cells and that they develop progressive lupus-like autoimmunity, with antibodies to chromatin, DNA, and IgG. The autoimmunity appears to be driven by endogenous antigens, with little polyclonal B cell activation. These mice should be an excellent model for studying the role of apoptotic debris as an immunogenic stimulus for systemic autoimmunity.

Subfields: Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/569669c794bba7ba291bf21d967083f1a3696935

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Citations in the corpus

• A role for Mer tyrosine kinase in αvβ5 integrin-mediated phagocytosis of apoptotic cells (2005, background): “Triple null mutants of Mer, Axl and Tyro3 develop a more penetrant phenotype, resulting in failure of apoptotic cell clearance in many tissues, and develop a severe autoimmune systemic lupus erythematosus (SLE)-like disease (Cohen et al., 2002; Lu et al., 1999).”
• Immunobiology of the TAM receptors (2008, background): “Bacterial and viral infections generate a large number of apoptotic-cell corpses, which must be cleared by macrophages and DCs, and this form of homeostatic phagocytosis is also impaired in the TAM-deficient mic”
• Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer (2016, background): “In the case of Mertk, which is abundantly expressed on M2macrophages and bone marrow-derivedDCs (BMDCs), the tyrosine kinase transmits a PS-dependent inhibitory signal that prevents LPS-inducible phosphorylation of IκB kinase, degradation of IκB, and the activation of NF-κB.49 This effect is Mertk-s”
• Apoptotic cells promote their own clearance and immune tolerance through activation of LXR (2009, positive): “The autoimmune phenotype of LXR-deficient mice is highly reminiscent of that of Mertk / mice (Cohen et al., 2002).”
• Efficient clearance of early apoptotic cells by human macrophages requires “M2c” polarization and MerTK induction (2012, background): “MerTK is expressed in primary and secondary lymphoid organs (7, 8) and is key for maintenance of both central and peripheral tolerance through multiple mechanisms: removal of AC-derived potential autoantigens (8, 16), inhibition of TLR-induced production of proinflammatory cytokines (17–19), and pre”
• Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. (2006, background): “Mer TK null mice also exhibit SLE-like pathology, where persistence of AC and necrotic bodies are proposed to lead to development of an inappropriate immune response to endogenous antigens (Cohen et al., 2002).”
• TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. (2007, background): “Several receptors that participate in the recognition of PS on the surface of apoptotic cells have been identified, and deficiencies of these molecules in mouse models lead to a failure to maintain self-tolerance and development of autoimmunity (Asano et al., 2004; Cohen et al., 2002).”
• Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. (2006, background): “Impairment in the phagocytosis of apoptotic and necrotic cells is known to induce autoimmune disease ( Cohen et al., 2002 ), and the protective effects of IgM DNA Abs have been clearly demonstrated in autoimmune NZB/W mice (Werwitzke et al., 2005).”
• TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. (2008, background): “TAM‐receptor knockouts develop autoimmune diseases, including rheumatoid arthritis and lupus (Cohen et al., 2002; Lemke and Lu, 2003).”
• The role of defective clearance of apoptotic cells in systemic autoimmunity (2010, background): “Genetic models in which the Mer kinase–liver X receptor pathway or the tissue transglutaminase type II or MGF-E8 molecules have been targeted further highlight the link between uncleared apoptotic cells and autoimmunity”