Cholinergic signaling via the [alpha]7 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation

Background The involvement of the autonomic nervous system in the regulation of inflammation is an emerging concept with significant potential for clinical applications. Recent studies demonstrate that stimulating the vagus nerve activates the cholinergic anti-inflammatory pathway that inhibits pro-inflammatory cytokines and controls inflammation. The [alpha]7 nicotinic acetylcholine receptor ([alpha]7nAChR) on macrophages plays a key role in mediating cholinergic anti-inflammatory effects through a downstream intracellular mechanism involving inhibition of NF-κB signaling, which results in suppression of pro-inflammatory cytokine production. However, the role of the [alpha]7nAChR in the regulation of other aspects of the immune response, including the recruitment of monocytes/macrophages to the site of inflammation remained poorly understood. Results We observed an increased mortality in [alpha]7nAChR-deficient mice (compared with wild-type controls) in mice with endotoxemia, which was paralleled with a significant reduction in the number of monocyte-derived macrophages in the lungs. Corroborating these results, fluorescently labeled [alpha]7nAChR-deficient monocytes adoptively transferred to WT mice showed significantly diminished recruitment to the inflamed tissue. [alpha]7nAChR deficiency did not affect monocyte 2D transmigration across an endothelial monolayer, but it significantly decreased the migration of macrophages in a 3D fibrin matrix. In vitro analysis of major adhesive receptors (L-selectin, [beta]1 and [beta]2 integrins) and chemokine receptors (CCR2 and CCR5) revealed reduced expression of integrin [alpha]M and [alpha]X on [alpha]7nAChR-deficient macrophages. Decreased expression of [alpha]M[beta]2 was confirmed on fluorescently labeled, adoptively transferred [alpha]7nAChR-deficient macrophages in the lungs of endotoxemic mice, indicating a potential mechanism for [alpha]7nAChR-mediated migration. Conclusions We demonstrate a novel role for the [alpha]7nAChR in mediating macrophage recruitment to inflamed tissue, which indicates an important new aspect of the cholinergic regulation of immune responses and inflammation. Keywords: Cholinergic anti-inflammatory pathway, [alpha]7nAChR, Macrophage, Migration, Endotoxemia, Sepsis