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A Defect in Marco Expression Contributes to Systemic Lupus Erythematosus Development via Failure to Clear Apoptotic Cells¹

Nicola Jane Rogers^2,3,*, Mark Jeffrey Lees^2,, Luisa Gabriel^*, Eleni Maniati^*, Sarah Jane Rose, Paul Keith Potter and Bernard John Morley

^* Immunology Department and Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, U.K.

Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the production of numerous antinuclear autoantibodies and inflammatory mediators. The BXSB mouse strain is an excellent model of the disease. Previous work has determined a number of important disease susceptibility intervals that have been isolated in separate congenic strains. Here, we have combined expression data from those strains with functional analyses to demonstrate that reduced expression of the innate scavenger receptor Marco (macrophage receptor with collagenous structure) is a primary event in BXSB mice, that reduced mRNA expression is mirrored at the protein level, and that this results in a significant alteration in function. We have confirmed a role for Marco in the clearance of apoptotic cells and a generalized defect in both endocytosis and phagocytosis. The failure to clear apoptotic cells has previously been linked to the development of systemic lupus erythematosus. However, the use of congenic mice with limited phenotypes in this study has enabled us to propose that in the case of Marco at least, disease results from the production of anti-dsDNA Abs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by a Programme Grant awarded to B.J.M. and N.J.R. by the Arthritis Research Campaign.

² N.J.R. and M.J.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Nicola Rogers, Immunology Department, Imperial College London., Hammersmith Campus, Du Dane Road, London, W12 0NN, U.K. E-mail address: nicola.rogers{at}imperial.ac.uk

⁴ Abbreviations used in this paper used in this paper: BMDM, bone marrow-derived macrophage; Marco, macrophage receptor with collagenous structure; MZM, marginal zone macrophage; SLE, systemic lupus erythematosus; qPCR, quantitative real-time PCR; Yaa, Y-linked autoimmune acceleration.