Macrophages from lupus-prone MRL mice are characterized by abnormalities in Rho activity, cytoskeletal organization, and adhesiveness to extracellular matrix proteins.
Macrophages (mphi) 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 mphi 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 mphi adhered in increased numbers to a variety of extracellular matrix proteins compared with mphi from two nonautoimmune strains. However, in the absence of serum, adhesion by MRL mphi was similar to that of nonautoimmune mphi. Increased adhesion by MRL mphi was also observed in the presence of apoptotic, but not necrotic, cells. The morphology and actin-staining pattern of adherent MRL mphi were consistent with reduced activity of Rho, a cytoskeletal regulator. Indeed, MRL mphi cultured in the presence of serum had markedly decreased levels of active Rho compared with nonautoimmune mphi. It is remarkable that when cultured in the absence of serum, MRL mphi displayed normal Rho activity and cytoskeletal morphology. Addition of a Rho inhibitor to normal mphi reproduced the morphologic and cytoskeletal abnormalities observed in MRL mphi. Taken together, our findings support the hypothesis that mphi from MRL and other systemic lupus erythematosus-prone mice have an apoptotic, cell-dependent, autoimmune phenotype that affects a broad range of mphi functions, including cytokine gene expression and Rho-dependent cytoskeletal regulation.
Section of Nephrology, Department of Medicine, The University of Illinois at Chigaco, Chicago, IL 60612, USA.
Angelika
A
Longacre
Jason S
JS
Koh
Kevin K-H
KK
Hsiao
Hannah
H
Gilligan
Hanli
H
Fan
Vimal A
VA
Patel
Jerrold S
JS
Levine
D000199:Actins / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016023:Integrins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D010641:Phenotype; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D000199:Actins; D001798:Blood Proteins; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D016023:Integrins; D020741:rho GTP-Binding Proteins