Cyclooxygenase-2 deficiency in macrophages leads to defective p110γ PI3K signaling and impairs cell, adhesion and migration

Abstract

Cyclooxygenase (Cox)-2 dependent PGs modulate several functions in many pathophysiological processes, including migration of immune cells. In this study, we addressed the role of Cox-2 in macrophage migration by using in vivo and in vitro models. Upon thioglycolate challenge, CD11b+ F4/80 + macrophages showed a diminished ability to migrate to the peritoneal cavity in cox-2-/- mice. In vivo migration of cox-2 -/- macrophages from the peritoneal cavity to lymph nodes, as well as cell adhesion to the mesothelium, was reduced in response to LPS. In vitro migration of cox-2-/- macrophages toward MCP-1, RANTES, MIP-1α, or MIP-1β, as well as cell adhesion to ICAM-1 or fibronectin, was impaired. Defects in cell migration were not due to changes in chemokine receptor expression. Remarkably, cox-2-/- macrophages showed a deficiency in focal adhesion formation, with reduced phosphorylation of paxillin (Tyr188). Interestingly, expression of the p110γ catalytic subunit of PI3K was severely reduced in the absence of Cox-2, leading to defective Akt phosphorylation, as well as cdc42 and Rac-1 activation. Our results indicate that the paxillin/p110γ-PI3K/Cdc42/Rac1 axis is defective in cox-2-/- macrophages, which results in impaired cell adhesion and migration. Copyright © 2013 by The American Association.Comunidad Autonoma de Madrid (S2010/BMD-2332); the Cardiovascular Red Temática de Investigacion en Enfermedades Cardiovasculares and Red de Investigacion Cooperativa en Enfermedades Tropicales Networks of the Instituto de Salud Carlos III (RD06/0014/1013 and RD06/0021/0016); the European Union (EICOSANOX LSH-CT-2004-005033); Ministerio de Ciencia e Innovacion (SAF2007-61716 and SAF2010-18733) and BFU2010-21055 and SAF2011-23971); Fondo de Investigacion Sanitaria; Fundacion Ramon ArecesPeer Reviewe