Noradrenaline modulates CD4+ T cell priming in rat experimental autoimmune encephalomyelitis: a role for the α1-adrenoceptor
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Pharmacological blockade of α1-adrenoceptor is shown to influence development of experimental autoimmune encephalomyelitis (EAE), an IL-17-producing CD4+TCR+ (Th17) cell-mediated disease mimicking multiple sclerosis. Considering significance of CD4+ cell priming for the clinical outcome of EAE, the study examined α1-adrenoceptor-mediated influence of catecholamines, particularly those derived from draining lymph node (dLN) cells (as catecholamine supply from nerve fibers decreases with the initiation of autoimmune diseases) for CD4+ cell priming. The results confirmed diminishing effect of immunization on nerve fiber-derived noradrenaline supply and showed that antigen presenting and CD4+ cells synthesize catecholamines, while antigen presenting cells and only CD4+CD25+Foxp3+ regulatory T cells (Tregs) express α1-adrenoceptor. The analysis of influence of α1-adrenoceptor antagonist prazosin on the myelin basic protein (MBP)-stimulated CD4+ lymphocytes in dLN cell culture showed their diminished proliferation in the presence of prazosin. This was consistent with prazosin enhancing effect on Treg frequency and their Foxp3 expression in these cultures. The latter was associated with upregulation of TGF-β expression. Additionally, prazosin decreased antigen presenting cell activation and affected their cytokine profile by diminishing the frequency of cells that produce Th17 polarizing cytokines (IL-1β and IL-23) and increasing that of IL-10-producing cells. Consistently, the frequency of all IL-17A+ cells and those co-expressing GM-CSF within CD4+ lymphocytes was decreased in prazosin-supplemented MBP-stimulated dLN cell cultures. Collectively, the results indicated that dLN cell-derived catecholamines may influence EAE development by modulating interactions between distinct subtypes of CD4+ T cells and antigen presenting cells through α1-adrenoceptor and consequently CD4+ T cell priming.
KeywordsNoradrenaline α1-Adrenoceptor EAE Tregs Th17 CD4+ lymphocyte proliferation
GL, ZSV, IP, and IV designed the study. GL, ZSV, and IV wrote the manuscript. GL, ZSV, IP, IV, RP, DK, MNA, and NJ participated in experiments, data analysis and/or interpretation, and critically reviewed and approved the manuscript.
This work was supported by the Ministry of Education, Science, and Technological Development of the Republic of Serbia (grant number 175050).
Compliance with ethical standards
All experimental procedures and animal care were performed in accordance with the Directive 2010/63/EU of the European Parliament and of the Council on the protection of animals used for scientific purposes (revising Directive 86/609/EEC) and approved by the Animal Care and Use Committee of the Faculty of Pharmacy (permit number 6/12). The experiments complied with the ARRIVE guidelines for reporting animal research.
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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