Participation of myeloid-derived suppressor cells in the PAFR-induced inhibition of contact hypersensitivity

Abstract

Myeloid-derived suppressor cells (MDSC) comprise a group of cells that modulates immune response by inducing Treg generation, by producing TGF-beta, IL-10, etc. We showed that apoptotic cells-induced regulatory profile in macrophages is dependent on platelet-activating factor receptor (PAFR), and that PAFR contributes to tumor growth. Travers and col described that the promotion of tumor growth by PAFR involves Treg cells generation and IL-10 production. Moreover, the same group showed that PAFR engagement inhibits contact hypersensitivity (CHS) in a Treg generation-dependent manner. These data show that PAFR is involved in modulation of immune response. However, the mechanisms underlying PAFR-induced immunosuppression are still unclear. We hypothesize that MDSC are generated/activated by PAFR engagement and this might contribute for the immune modulator feature of this receptor. In this project, we intend to evaluate whether (and how) MDSC are involved in the mechanisms of PAFR-dependent inhibition of CHS. For that, we will use a well-established model of induction of lipid oxidation in vivo using environmental stressors. WT and PAFR KO mice will be irradiated with ultraviolet (UV) or exposed to cigarette smoke (CS) (environmental stressors that generate PAFR ligands) before induction of (CHS) in the ear with dinitrofluorobenzene. The amounts of MDSC in the spleen and ear will be assessed by flow cytometry and compared between PAFR KO and WT mice. In parallel, MDSC will be screened and analyzed for detection of PAFR expression. To assess the role of MDSC on the PAFR-dependent inhibition of CHS, Gr1+ cells (MDSC) will be depleted in PAFR KO and WT mice using antibody before UV radiation or CS exposure. The frequency of Treg cells and/or FOXP3 expression in lymph nodes will be assessed and the ear thickness will be measured. To evaluate whether Treg cells contribute to MDSC generation or activation, CD25+ cells will be depleted and amounts of MDSC will be assessed. In all cases, splenocytes will be harvested for culture and detection of LPS-stimulated cytokine for evaluation of activation profile (M1/M2). (AU)