title: β2-Adrenoreceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system.
abstract: The nervous system is classically organized into sympathetic and parasympathetic systems acting in opposition to maintain physiological homeostasis. Here, we report that both systems converge in the activation of β2-adrenoceptors of splenic regulatory lymphocytes to control systemic inflammation. Vagus nerve stimulation fails to control serum TNF levels in either β2-knockout or lymphocyte-deficient nude mice. Unlike typical suppressor CD25(+) cells, the transfer of CD4(+)CD25(-) regulatory lymphocytes reestablishes the anti-inflammatory potential of the vagus nerve and β2-agonists to control inflammation in both β2-knockout and nude mice. β2-Agonists inhibit cytokine production in splenocytes (IC(50)≈ 1 μM) and prevent systemic inflammation in wild-type but not in β2-knockout mice. β2-Agonists rescue wild-type mice from established polymicrobial peritonitis in a clinically relevant time frame. Regulatory lymphocytes reestablish the anti-inflammatory potential of β2-agonists to control systemic inflammation, organ damage, and lethal endotoxic shock in β2-knockout mice. These results indicate that β2-adrenoceptors in regulatory lymphocytes are critical for the anti-inflammatory potential of the parasympathetic vagus nerve, and they represent a potential pharmacological target for sepsis.
authors.affiliation: Laboratory of Immunity and Infection, Department of Surgery, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103, USA.
authors.forename: Gergely
authors.initials: G
authors.lastname: Vida
authors.forename: Geber
authors.initials: G
authors.lastname: Peña
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kanashiro
authors.forename: Maria del Rocio
authors.initials: Mdel R
authors.lastname: Thompson-Bonilla
authors.forename: David
authors.initials: D
authors.lastname: Palange
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Luis
authors.initials: L
authors.lastname: Ulloa
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D019446:Endotoxemia / Q000276:immunology / Q000503:physiopathology; D006439:Hemodynamics; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D015213:Neuroimmunomodulation; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D018805:Sepsis / Q000276:immunology / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014630:Vagus Nerve / Q000276:immunology
chemical_list: D016207:Cytokines; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D009638:Norepinephrine