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Published online before print August 17, 2004

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(Journal of Leukocyte Biology. 2004;76:971-984.)
© 2004 by Society for Leukocyte Biology

Macrophages from lupus-prone MRL mice are characterized by abnormalities in Rho activity, cytoskeletal organization, and adhesiveness to extracellular matrix proteins

Section of Nephrology, Department of Medicine, The University of Illinois at Chicago

² Correspondence: The University of Illinois at Chicago, Section of Nephrology, 820 South Wood Street, MC-793, Room 479/CSN, Chicago, IL 60612. E-mail: jslevine{at}uic.edu

Macrophages (m) from prediseased mice of the major murine models of lupus have an identical defect in cytokine expression that is triggered by serum and/or apoptotic cells. It is striking that cytokine expression in the absence of serum and apoptotic cells is equivalent to that of nonautoimmune mice. Here, we show that m from prediseased lupus-prone MRL/MpJ (MRL/+) or MRL/MpJ-Tnfrsf6^lpr (MRL/lpr) mice also have reversible abnormalities in morphology, cytoskeletal organization, and adhesive properties. In the presence of serum, MRL m adhered in increased numbers to a variety of extracellular matrix proteins compared with m from two nonautoimmune strains. However, in the absence of serum, adhesion by MRL m was similar to that of nonautoimmune m. Increased adhesion by MRL m was also observed in the presence of apoptotic, but not necrotic, cells. The morphology and actin-staining pattern of adherent MRL m were consistent with reduced activity of Rho, a cytoskeletal regulator. Indeed, MRL m cultured in the presence of serum had markedly decreased levels of active Rho compared with nonautoimmune m. It is remarkable that when cultured in the absence of serum, MRL m displayed normal Rho activity and cytoskeletal morphology. Addition of a Rho inhibitor to normal m reproduced the morphologic and cytoskeletal abnormalities observed in MRL m. Taken together, our findings support the hypothesis that m from MRL and other systemic lupus erythematosus-prone mice have an apoptotic, cell-dependent, autoimmune phenotype that affects a broad range of m functions, including cytokine gene expression and Rho-dependent cytoskeletal regulation.

Key Words: rodent • autoimmunity

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