Kinin B2 receptor regulates chemokines CCL2 and CCL5 expression and modulates leukocyte recruitment and pathology in experimental autoimmune encephalomyelitis (EAE) in mice

Background: Kinins are important mediators of inflammation and act through stimulation of two receptor subtypes, B-1 and B-2. Leukocyte infiltration contributes to the pathogenesis of autoimmune inflammation in the central nervous system (CNS), occurring not only in multiple sclerosis ( MS) but also in experimental autoimmune encephalomyelitis (EAE). We have previously shown that the chemokines CCL2 and CCL5 play an important role in the adhesion of leukocytes to the brain microcirculation in EAE. The aim of the present study was to evaluate the relevance of B2 receptors to leukocyte-endothelium interactions in the cerebral microcirculation, and its participation in CNS inflammation in the experimental model of myelin-oligodendrocyte-glycoprotein (MOG)(35-55)-induced EAE in mice. Methods: In order to evaluate the role of B2 receptor in the cerebral microvasculature we used wildtype (WT) and kinin B2 receptor knockout (B-2(-/-)) mice subjected to MOG(35-55)-induced EAE. Intravital microscopy was used to investigate leukocyte recruitment on pial matter vessels in B-2(-/-) and WT EAE mice. Histological documentation of inflammatory infiltrates in brain and spinal cords was correlated with intravital findings. The expression of CCL5 and CCL2 in cerebral tissue was assessed by ELISA. Results: Clinical parameters of disease were reduced in B-2(-/-) mice in comparison to wild type EAE mice. At day 14 after EAE induction, there was a significant decrease in the number of adherent leukocytes, a reduction of cerebral CCL5 and CCL2 expressions, and smaller inflammatory and degenerative changes in B-2(-/-) mice when compared to WT. Conclusion: Our results suggest that B-2 receptors have two major effects in the control of EAE severity: (i) B-2 regulates the expression of chemokines, including CCL2 and CCL5, and (ii) B-2 modulates leukocyte recruitment and inflammatory lesions in the CNS.