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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Mononuclear Cell Extravasation in an Inflammatory Response Is Abrogated by All-Trans-Retinoic Acid through Inhibiting the Acquisition of an Appropriate Migratory Phenotype

Department of Pathology, University Hospital Ramón y Cajal, Universidad de Alcalá, Madrid, Spain (M.M.E., E.C., D.S.-M., M.L.G.-B.); and Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands (P.L.H.)

The inflammatory response is tightly regulated by several mediators that promote the adhesive and migratory capacities of different cell types, including peripheral blood mononuclear cells (PBMCs). Our laboratory has previously characterized the inflammatory response developed in the experimental model of mercuric chloride (HgCl₂)-induced nephritis in Brown Norway rats as an acute inflammatory response dependent on very late antigen (VLA)-4. This response can be modulated by all-trans-retinoic acid (at-RA), a vitamin A metabolite that regulates a broad range of biological processes and exhibits anti-inflammatory properties. Based on this in vivo experimental model, we have established a VLA-4-dependent ex vivo system to study the effect of at-RA on PBMC polarization, adhesion, and migration and to elicit new mechanisms triggered by at-RA for abrogating an inflammatory response. We found that at-RA significantly reduces the VLA-4-dependent migration of PBMCs activated in vivo. In addition, we demonstrated by spreading assays that in vivo at-RA treatment abrogates the acquisition of a polarized cell phenotype. In fact, at-RA inhibits the actin polymerization required for cell morphology changes, and it alters the distribution of F-actin and VLA-4 integrin in focal contacts, essential for cell adhesion. Moreover, we describe that at-RA also abrogates the redistribution of Rac1 and RhoA, important proteins implicated in the dynamic process of cell movement. In summary, we demonstrate the capacity of at-RA to block the acquisition of an appropriate migratory phenotype in PBMCs as a new mechanism underlying the anti-inflammatory effects of this compound.

Address correspondence to: Dr. María Laura García-Bermejo, Department of Pathology, University Hospital Ramón y Cajal, Carretera de Colmenar, Km 9.1, 28034 Madrid, Spain. E-mail: mgarciab.hrc{at}salud.madrid.org