Propranolol influences EAE development by impairing antigen presenting cell migration into the draining lymph nodes

Abstract

Introduction: Catecholamines are implicated in development of multiple sclerosis and EAE in Dark Agouti (DA) rats. To enlighten their β−adrenoceptor−mediated immunomodulatory action, DA rats of both sexes immunized for EAE were subjected to seven−day−long treatment with propranolol (β−adrenoceptor blocker) starting at the day of immunization. Methods: The migration of antigen presenting cells (APCs) into the draining lymph nodes (dLNs) was examined using CFSE−based assay. Frequency of activated CD4+ T cells, their proliferation and frequency of IL−17−producing CD4+ T (Th17) cells in dLNs, and their infiltration into spinal cord, were analyzed using flow cytometry. Propranolol effects on CD4+ cell proliferation and Th17 cell polarization, and IL−2 and Th17 polarizing cytokine and chemokine expression in dLNs/ dLN cell cultures were examined using flow cytometry and ELISA/qRT−PCR. Results: Irrespective of sex, propranolol reduced the incidence and postponed clinical EAE onset by impairing migration of antigen−carrying APCs into the dLNs (due to diminished dLN CCL19/21 expression). Consequently, propranolol diminished CD4+ T−cell activation/proliferation, and Th17 cell number in dLNs and spinal cord. To corroborate these findings, propranolol exerted stimulatory effects on CD4+ cell proliferation (through stimulation of IL−2 secretion) and Th17 cell differentiation (reflecting enhanced Th17 polarizing cytokine production) in dLN cell cultures. Conclusions: Irrespective of sex, the stimulatory effects of propranolol on dLN CD4+ T lymphocyte proliferation and activated/ matured APC Th17 polarizing capacity were insufficient to overcome its inhibitory influence on APC migration, so propranolol impaired Th17 generation in dLNs of EAE rats, and postponed EAE development.