title: 5'-AMP impacts lymphocyte recirculation through activation of A2B receptors.
abstract: Natural hibernation consists of torpid phases with metabolic suppression alternating with euthermic periods. Induction of torpor holds substantial promise in various medical conditions, including trauma, major surgery, and transplantation. Torpor in mice can be induced pharmacologically by 5'-AMP. Previously, we showed that during natural torpor, the reduction in body temperature results in lymphopenia via a reduction in plasma S1P. Here, we show that during torpor induced by 5'-AMP, there is a similar reduction in the number of circulating lymphocytes that is a result of their retention in secondary lymphoid organs. This lymphopenia could be mimicked by engagement of A(2B)Rs by a selective A(2B)R agonist (LUF6210) in the absence of changes in temperature and prevented by A(2B)R antagonists during 5'-AMP-induced torpor. In addition, forced cooling of mice led to peripheral blood lymphopenia, independent of A(2B)R signaling. The induction of torpor using 5'-AMP impacted the migration of lymphocytes within and between secondary lymphoid organs. During torpor, the homing into LNs was impaired, and two-photon intravital microscopy revealed that cell motility was decreased significantly and rapidly upon 5'-AMP administration. Furthermore, the S1P plasma concentration was reduced by 5'-AMP but not by LUF6210. S1P plasma levels restored upon arousal. Likely, the reduced migration in LNs combined with the reduced S1P plasma level substantially reduces lymphocyte egress after injection of 5'-AMP. In conclusion, 5'-AMP induces a state of pharmacological torpor in mice, during which, lymphopenia is governed primarily by body temperature-independent suppression of lymphocyte egress from LNs.
authors.affiliation: University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. h.r.bouma@umcg.nl
authors.forename: Hjalmar R
authors.initials: HR
authors.lastname: Bouma
authors.forename: Judith N
authors.initials: JN
authors.lastname: Mandl
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Strijkstra
authors.forename: Ate S
authors.initials: AS
authors.lastname: Boerema
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Kok
authors.forename: Annie
authors.initials: A
authors.lastname: van Dam
authors.forename: Ad
authors.initials: A
authors.lastname: Ijzerman
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Kroese
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
mesh_terms: D000249:Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D005434:Flow Cytometry; D006605:Hibernation / Q000187:drug effects* / Q000502:physiology; D008214:Lymphocytes / Q000187:drug effects*; D008231:Lymphopenia / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D043704:Receptor, Adenosine A2B / Q000378:metabolism*
chemical_list: D043704:Receptor, Adenosine A2B; D000249:Adenosine Monophosphate; D002118:Calcium
keywords: anesthesiology; hibernation; inflammation; metabolism; suspended animation