Neural control of acetylcholine release by T cells attenuates TNF production in endotoxemia (138.24)

Abstract

Abstract The cholinergic anti-inflammatory pathway regulates pro-inflammatory cytokine production through vagus nerve signaling via the α7 subunit of the nicotinic acetylcholine receptor expressed on macrophages. Vagus nerve stimulation requires an intact splenic nerve to attenuate TNF production by spleen macrophages. Despite exhaustive search, cholinergic fibers have not been observed in spleen. Here, we used transgenic mice that express enhanced green fluorescent protein (eGFP) under control of transcriptional regulatory elements of choline acetyltransferase, the enzyme that synthesizes acetylcholine. eGFP was detected in spleen B and T cells, some of which were located in close proximity to catecholaminergic nerve endings in the parenchyma of the white pulp. Vagus nerve stimulation significantly increased acetylcholine levels in spleen. In vitro, adrenergic stimulation induced the release of acetylcholine by spleen lymphocytes through a β2 adrenergic receptor dependent mechanism. Vagus nerve stimulation failed to suppress TNF in endotoxemic nude mice, and transfer of CD3+ T cells into nude mice restored vagus nerve control of cytokine production. Together, these data identify T cells as an essential component of the cholinergic anti-inflammatory pathway, and suggest that neural signals increase acetylcholine release from spleen T cells, which in turn attenuates TNF production in spleen via α7 expressed on innate immune cells.