The GTPase Rap1 controls functional activation of macrophage integrin alphaMbeta2 by LPS and other inflammatory mediators.
BACKGROUND
beta2 integrins mediate many aspects of the inflammatory and immune responses, including adhesion of leukocytes to the endothelium, complement-mediated phagocytosis in macrophages and neutrophils, and antigen-specific conjugate formation between cytotoxic T cells and their targets. A variety of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), platelet-activating factor (PAF), and lipopolysaccharide (LPS) and other bacterial products induce the functional activation of beta2 integrins, but the signaling events that link membrane receptors to integrin activation are poorly understood.


RESULTS
We report here that expression of the constitutively active small GTPases Rap1 or R-ras, but not Ras or RalA, is sufficient for functional activation of alphaMbeta2, the complement receptor 3 (CR3), in macrophages, allowing phagocytosis of C3bi-opsonized targets. Inhibition of Rap1, but not other Ras-like or Rho-like small GTPases, abolishes activation of alphaMbeta2 induced by phorbol esters, LPS, TNF-alpha or PAF. Finally, Rap1 activation specifically controls the binding properties of alphaMbeta2 towards its physiological ligand, namely the complement-opsonized phagocytic targets.


CONCLUSIONS
In macrophages, the Rap1 GTPase regulates activation of the alphaMbeta2 integrin in response to a wide variety of inflammatory mediators.
Caron
E
E
Medical Research Council Laboratory for Molecular Cell Biology, University College London, UK.
Self
A J
AJ
Hall
A
A
D000818:Animals; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008262:Macrophage Activation; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D011993:Recombinant Fusion Proteins; D020558:GTP Phosphohydrolases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins