The β 1 -Adrenergic Receptor Contributes to Sepsis-Induced Immunosuppression Through Modulation of Regulatory T-Cell Inhibitory Function.

Objectives: Although cardiovascular benefits of β 1 -adrenergic receptor blockade have been described in sepsis, little is known about its impact on the adaptive immune response, specifically CD4 T cells. Herein, we study the effects of β 1 -adrenergic receptor modulation on CD4 T-cell function in a murine model of sepsis.
Design: Experimental study.
Setting: University laboratory.
Subjects: C57BL/6 mice.
Interventions: High-grade sepsis was induced by cecal ligation and puncture in wild-type mice (β 1+/+ ) with or without esmolol (a selective β 1 -adrenergic receptor blocker) or in β 1 -adrenergic receptor knockout mice (β 1-/- ). At 18 hours after surgery, echocardiography was performed with blood and spleen collected to analyze lymphocyte function.
Measurements and Main Results: At 18 hours, β 1+/+ cecal ligation and puncture mice exhibited characteristics of high-grade sepsis and three surrogate markers of immunosuppression, namely decreased splenic CD4 T cells, reduced CD4 T-cell proliferation, and increased regulatory T lymphocyte cell proportions. Pharmacologic and genetic β 1 -adrenergic receptor blockade reversed the impact of sepsis on CD4 T and regulatory T lymphocyte proportions and maintained CD4 T-cell proliferative capacity. β 1 -adrenergic receptor blocked cecal ligation and puncture mice also exhibited a global decrease in both pro- and anti-inflammatory mediators and improved in vivo cardiovascular efficiency with maintained cardiac power index despite the expected decrease in heart rate.
Conclusions: β 1 -adrenergic receptor activation enhances regulatory T lymphocyte inhibitory function and thus contributes to sepsis-induced immunosuppression. This can be attenuated by β 1 -adrenergic receptor blockade, suggesting a potential immunoregulatory role for this therapy in the management of sepsis.
Competing Interests: Dr. Durand’s institution received funding from the Fondation pour la Recherche Médicale (FRM grant number ECO20170637495). Dr. Asfar received funding from GlaxoSmithKline. Dr. Singer’s institution received funding from Biotest, Deltex, and NewB; he received funding from Biotest, Biomerieux, Fresenius, General Electric, Nestle, NewB Diagnostics, Pfizer, and Shionogi. Drs. Singer and Levy received funding from Amomed. Dr. Singer received funding from Roche. Dr. Levy received funding from Gettinge, Novartis, Baxter, Amomed, Orion, and Sanofi. Dr. Kimmoun received funding from Aguettant. Dr. Glenn Chousterman received fees as a member of an advisory board from Roche Diagnostics. The remaining authors have disclosed that they do not have any potential conflicts of interest.
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