title: Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury.
abstract: Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R(-/-)) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain-infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A1R(-/-) mice displayed larger infarctions (+33%, p < 0.05) and performed worse in beam walking tests (44% more mistakes, p < 0.05) than wild-type (WT) mice. Myeloid cell activation after injury was enhanced in A1R(-/-) versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A1R(-/-). Also, A1R(-/-) B lymphocytes expressed less IL-10 than their WT counterparts, the A1R antagonist DPCPX decreased IL-10 expression whereas the A1R agonist CPA increased it. CD4(+) T lymphocytes including FoxP3(+) T regulatory cells, were unaffected by genotype, whereas CD8(+) T lymphocyte responses were smaller in A1R(-/-) mice. Using PCA to characterize the immune profile, we could discriminate the A1R(-/-) and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A1R signaling modulates IL-10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI.
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, 17176, Stockholm, Sweden. max.winerdal@medsci.se.
authors.forename: Max
authors.initials: M
authors.lastname: Winerdal
authors.affiliation: Department of Medicine, Karolinska Institutet, 17176, Stockholm, Sweden. malin.winerdal@ki.se.
authors.forename: Malin E
authors.initials: ME
authors.lastname: Winerdal
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17176, Stockholm, Sweden. yqwang001@sina.com.|Neonatal Research Unit Q2:07, Karolinska Universitetssjukhuset Solna, 17176, Stockholm, Sweden. yqwang001@sina.com.
authors.forename: Ying-Qing
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17176, Stockholm, Sweden. bertil.fredholm@ki.se.
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Fredholm
authors.affiliation: Department of Medicine, Karolinska Institutet, 17176, Stockholm, Sweden. ola.winqvist@karolinska.se.|Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, People's Republic of China. ola.winqvist@karolinska.se.
authors.forename: Ola
authors.initials: O
authors.lastname: Winqvist
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, 17176, Stockholm, Sweden. ulrika.aden@ki.se.|Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, People's Republic of China. ulrika.aden@ki.se.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Ådén
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000276:immunology*; D002545:Brain Ischemia / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology; D005260:Female; D002534:Hypoxia, Brain / Q000151:congenital / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004856:Postural Balance; D011247:Pregnancy; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000276:immunology*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; C556062:IL10 protein, mouse; D043682:Receptor, Adenosine A1; D016753:Interleukin-10
keywords: Adenosine A1 receptor; Brain hypoxic-ischemia; Cellular immunity; Neonatology; Neuroimmunomodulation; Statistical data interpretation