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

Macrophages (mφ) 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 mφ from prediseased lupus‐prone MRL/MpJ (MRL/+) or MRL/MpJ‐Tnfrsf6lpr (MRL/lpr) mice also have reversible abnormalities in morphology, cytoskeletal organization, and adhesive properties. In the presence of serum, MRL mφ adhered in increased numbers to a variety of extracellular matrix proteins compared with mφ from two nonautoimmune strains. However, in the absence of serum, adhesion by MRL mφ was similar to that of nonautoimmune mφ. Increased adhesion by MRL mφ was also observed in the presence of apoptotic, but not necrotic, cells. The morphology and actin‐staining pattern of adherent MRL mφ were consistent with reduced activity of Rho, a cytoskeletal regulator. Indeed, MRL mφ cultured in the presence of serum had markedly decreased levels of active Rho compared with nonautoimmune mφ. It is remarkable that when cultured in the absence of serum, MRL mφ displayed normal Rho activity and cytoskeletal morphology. Addition of a Rho inhibitor to normal mφ reproduced the morphologic and cytoskeletal abnormalities observed in MRL mφ. Taken together, our findings support the hypothesis that mφ from MRL and other systemic lupus erythematosus‐prone mice have an apoptotic, cell‐dependent, autoimmune phenotype that affects a broad range of mφ functions, including cytokine gene expression and Rho‐dependent cytoskeletal regulation.