title: Blocking A2B adenosine receptor alleviates pathogenesis of experimental autoimmune encephalomyelitis via inhibition of IL-6 production and Th17 differentiation.
abstract: Adenosine is a key endogenous signaling molecule that regulates immune responses. A(2B) adenosine receptor (AR) is a relatively low-affinity receptor for adenosine, and the activation of A(2B)AR is believed to require pathological level of adenosine that is associated with ischemia, inflammation, trauma, or other types of stress. The role of A(2B)AR in the pathogenesis of multiple sclerosis (MS) is still unclear. In this study, we discovered that A(2B)AR was upregulated both in the peripheral blood leukocytes of MS patients and the peripheral lymphoid tissues of experimental autoimmune encephalomyelitis (EAE) mice. A(2B)AR-specific antagonists, CVT-6883 and MRS-1754, alleviated the clinical symptoms of EAE and protected the CNS from immune damage. A(2B)AR-knockout mice also developed less severe EAE. Further study indicated that blocking or deleting A(2B)AR inhibited Th17 cell differentiation by blocking IL-6 production from APCs such as dendritic cells. In dendritic cells, A(2B)AR was also upregulated during the development of EAE. CVT-6883 and genetic deletion of A(2B)AR significantly reduced adenosine-mediated IL-6 production. The phospholipase Cβ-protein kinase C and p38 MAPK pathways were found to be involved in the A(2B)AR-mediated IL-6 production. Our findings not only revealed the pathological role of A(2B)AR in EAE, but also suggested that this receptor might be a new therapeutic target for the development of anti-MS drugs.
authors.affiliation: Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Changsheng
authors.initials: C
authors.lastname: Du
authors.forename: Jie
authors.initials: J
authors.lastname: Lv
authors.forename: Guixian
authors.initials: G
authors.lastname: Zhao
authors.forename: Zhenxin
authors.initials: Z
authors.lastname: Li
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Wu
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D043704:Receptor, Adenosine A2B / Q000172:deficiency / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
chemical_list: D006131:Growth Inhibitors; D015850:Interleukin-6; D043704:Receptor, Adenosine A2B; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C577686:interleukin-6, mouse