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

Abstract

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.

Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β

“…In addition, infusion of 1 Â 10 7 -3 Â 10 7 ACs gains the best protection against hepatitis, suggesting redundant ACs beyond the clearance ability of KCs may become necrotic in the liver. Accordingly as described, 35,36 dysfunction of AC clearance may result in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus or diabetes.…”

The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis

“…It is noteworthy that anti-MARCO antibodies were detected in a transgenic mouse model of SLE; these antibodies were present at very early stages, before the onset of the disease. Moreover, THE SRCR SUPERFAMILY IN THERAPY AND DIAGNOSIS MARCO expression was shown to be down-regulated in spleen macrophages in a transgenic mouse model of SLE (Rogers et al, 2009). Macrophages derived from these mice also showed impaired ability to take up apoptotic cells, a consequence of an overall decrease in their phagocytic activity.…”

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

“…The MZ is populated by specialized MΦs tightly associated with the reticular meshwork. These MΦ are defined by constitutive expression of either the scavenger macrophage receptor with collagenous structure, MARCO, or the metallophillic macrophage marker, MOMA-1 (4)(5)(6). The importance of MZ MΦs (MZMs) in apoptotic cell removal and tolerance was illustrated by our recent findings that their depletion significantly changed the immune response to apoptotic cells altering localization, increasing proinflammatory cytokine production, and enhancing phagocytosis and phagocyte activation (7).…”