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Macrophage Migration Inhibitory Factor Deficiency Attenuates Macrophage Recruitment, Glomerulonephritis, and Lethality in MRL/lpr Mice¹

Department of Medicine, Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash University, Melbourne, Australia

Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disease of unknown etiology. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is operative in innate and adaptive immunity and important in immune-mediated diseases such as rheumatoid arthritis and atherosclerosis. The functional relevance of MIF in systemic autoimmune diseases such as SLE is unknown. Using the lupus-prone MRL/lpr mice, we aim to examine the expression and function of MIF in this murine model of systemic autoimmune disease. These experiments revealed that renal MIF expression was significantly higher in MRL/lpr mice compared with nondiseased control mice (MRL/MpJ), and MIF was also markedly up-regulated in skin lesions of MRL/lpr mice. To examine the effect of MIF on development of systemic autoimmune disease, we generated MRL/lpr mice with a targeted disruption of the MIF gene (MIF^–/–MRL/lpr), and compared their disease manifestations to MIF^+/+MRL/lpr littermates. MIF^–/–MRL/lpr mice exhibited significantly prolonged survival, and reduced renal and skin manifestations of SLE. These effects occurred in the absence of major changes in T and B cell markers or alterations in autoantibody production. In contrast, renal macrophage recruitment and glomerular injury were significantly reduced in MIF^–/–MRL/lpr mice, and this was associated with reduction in the monocyte chemokine MCP-1. Taken together, these data suggest MIF as a critical effector of organ injury in SLE.

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 work was supported by Program Grant 334067 from the National Health and Medical Research Council, Australia, and National Institutes of Health R01 Grant AR51807-01. A.Y.H. was supported by a postgraduate scholarship from the National Health and Medical Research Council.

² M.J.H. and E.F.M. contributed equally to this work.

³ Address correspondence and reprint requests to Assoc. Prof. Eric F. Morand, Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash University, Locked Bag Number 29, Clayton, Melbourne, Victoria, 3168, Australia. E-mail address: eric.morand{at}med.monash.edu.au

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; MIF, macrophage migration inhibitory factor; DNTC, double-negative T cell.

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