The GTPase Rap1 controls functional activation of macrophage integrin αMβ2 by LPS and other inflammatory mediators

Background: beta 2 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 beta 2 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 alpha M beta 2, 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 alpha M beta 2 induced by phorbol esters, LPS, TNF-alpha or PAF. Finally, Rap1 activation specifically controls the binding properties of alpha M beta 2 towards its physiological ligand, namely the complement-opsonized phagocytic targets. Conclusions: In macrophages, the Rap1 GTPase regulates activation of the alpha M beta 2 integrin in response to a wide variety of inflammatory mediators.