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

Cohen, Philip L; Caricchio, Roberto; Abraham, Valsamma; Camenisch, Todd D; Jennette, J Charles; Roubey, Robert A.S.; Earp, H. Shelton; Matsushima, Glenn; Reap, Elizabeth A.

doi:10.1084/jem.20012094

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

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Author(s): Philip L. Cohen ¹ , Roberto Caricchio ¹ , Valsamma Abraham ¹ , Todd D. Camenisch ² , J. Charles Jennette ³ , Robert A.S. Roubey ⁴ , H. Shelton Earp ⁴ , Glenn Matsushima ⁵ , Elizabeth A. Reap ⁶

Publication date (Print): 1 July 2002

Journal: The Journal of Experimental Medicine

Publisher: The Rockefeller University Press

Keywords: autoimmunity, Lupus Erythematosus, systemic, phagocytosis, apoptosis, macrophages

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Abstract

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.

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Most cited references 22

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Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.

M Botto, C Dell'Agnola, A E Bygrave … (1998)

The complement system plays a paradoxical role in the development and expression of autoimmunity in humans. The activation of complement in systemic lupus erythematosus (SLE) contributes to tissue injury. In contrast, inherited deficiency of classical pathway components, particularly C1q (ref. 1), is powerfully associated with the development of SLE. This leads to the hypothesis that a physiological action of the early part of the classical pathway protects against the development of SLE (ref. 2) and implies that C1q may play a key role in this respect. C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months. C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.

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Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family.

Q. Lu, G Lemke (2001)

Receptor tyrosine kinases and their ligands mediate cell-cell communication and interaction in many organ systems, but have not been known to act in this capacity in the mature immune system. We now provide genetic evidence that three closely related receptor tyrosine kinases, Tyro 3, Axl, and Mer, play an essential immunoregulatory role. Mutant mice that lack these receptors develop a severe lymphoproliferative disorder accompanied by broad-spectrum autoimmunity. These phenotypes are cell nonautonomous with respect to lymphocytes and result from the hyperactivation of antigen-presenting cells in which the three receptors are normally expressed.

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A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock.

T D Camenisch, B H Koller, H S Earp … (1999)

The regulation of monocyte function and the inhibition of TNF-alpha production during bacterial sepsis are critical in attenuating adverse host responses to endotoxemia. To study the function of a novel receptor tyrosine kinase, mer, that is expressed in monocytes, we generated mice (merkd) that lack the signaling tyrosine kinase domain. Upon LPS challenge, merkd animals died of endotoxic shock (15/17, 88.2%), whereas control wild-type mice survived (1/15, 6.7% died). Susceptible merkd mice exhibited edema, leukocyte infiltration, and signs of endotoxic shock that correlated with higher levels of TNF-alpha found in the serum of merkd mice as compared with wild-type control animals. Death due to LPS-induced endotoxic shock in merkd mice was blocked by administration of anti-TNF-alpha Ab, suggesting that overproduction of this cytokine was principally responsible for the heightened suseptibility. The increase in TNF-alpha production appeared to be the result of a substantial increase in the LPS-dependent activation of NF-kappa B nuclear translocation resulting in greater TNF-alpha production by macrophages from merkd mice. Thus, Mer receptor tyrosine kinase signaling participates in a novel inhibitory pathway in macrophages important for regulating TNF-alpha secretion and attenuating endotoxic shock.

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Author and article information

Journal

Journal ID (nlm-ta): J Exp Med

Title: The Journal of Experimental Medicine

Publisher: The Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date (Print): 1 July 2002

Volume: 196

Issue: 1

Pages: 135-140

Affiliations

[1 ]Department of Medicine, Division of Rheumatology, University of Pennsylvania, and Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104

[2 ]Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ 85259

[3 ]Department of Pathology, University of North Carolina, Chapel Hill, NC 27599

[4 ]Department of Medicine, University of North Carolina, Chapel Hill, NC 27599

[5 ]Department of Microbiology/Immunology, University of North Carolina, Chapel Hill, NC 27599

[6 ]AlphaVax, Durham, NC 27709

Author notes

Address correspondence to P.L. Cohen, Department of Medicine, Division of Rheumatology, University of Pennsylvania, 421 Curie Boulevard, Suite 757, Philadelphia, PA 19104. Phone: 215-573-2956; Fax: 215-573-7599; E-mail: philipco@ 123456mail.med.upenn.edu

Article

Publisher ID: 20012094

DOI: 10.1084/jem.20012094

PMC ID: 2194017

PubMed ID: 12093878

SO-VID: 46f6f6a2-76d8-4b5d-b0df-d640f6654678

History

Date received : 18 December 2001

Date revision received : 18 April 2002

Date accepted : 6 May 2002

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