The cholinergic anti-inflammatory pathway inhibits inflammation without lymphocyte relay

• DOI: 10.3389/fnins.2023.1125492
• Publication Date: 2023-04-14T04:56:41Z
• Authors: Thomas Simon; Joseph Kirk; Nikola Dolezalova; Mélanie Guyot; Clara Panzolini; Alexandre Bondue; Julien Lavergne; Sandrine Hugues; Nicolas Hypolite; Kourosh Saeb-Parsy; Justin Perkins; Eric Macia; Arun Sridhar; Margriet J. Vervo...; Nicolas Glaichenhaus; Matteo Donegá; Philippe Blancou
• Keywords: myeloid cells; splenic nerve stimulation; Neurosciences. Biological psychiatry. Neuropsychiatry; cholinergic anti-inflammatory pathway; CD4+ T lymphocytes; beta2 adrenergic receptor; RC321-571; Neuroscience

The magnitude of innate inflammatory immune responses is dependent on interactions between peripheral neural and cells. In particular, a cholinergic anti-inflammatory pathway (CAP) has been identified in the spleen whereby noradrenaline (NA) released by splenic nerves binds to ß2-adrenergic receptors (β2-AR) CD4+ T cells which, turn, release acetylcholine (ACh). binding ACh α7 (α7-AChR) expressed macrophages inhibits production cytokines, including tumor necrosis factor (TNF). However, role ACh-secreting T-cells CAP still controversial largely based absence this mice lacking (nude, FoxN1-/-). Using four conscious, non-lymphopenic transgenic mouse models, we found that, rather than acting T-cells, NA nerve terminals acts directly onto β2-AR myeloid exert effect. We also show while larger doses LPS are needed trigger nude strain compared other strains, TNF can be inhibited these animals T-cell stimulating either vagus or nerve. demonstrate that dispensable for after antibody-mediated depletion wild type mice. Furthermore, NA-mediated inhibition vitro LPS-induced secretion human porcine splenocytes does not require α7-AChR signaling. Altogether our data activation stimulation mainly mediated direct macrophages, suggest same mechanism at play species.