| First Author | Keever KR | Year | 2024 |
| Journal | J Neuroinflammation | Volume | 21 |
| Issue | 1 | Pages | 3 |
| PubMed ID | 38178134 | Mgi Jnum | J:344282 |
| Mgi Id | MGI:7571896 | Doi | 10.1186/s12974-023-03001-7 |
| Citation | Keever KR, et al. (2024) Cholinergic signaling via the alpha7 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation. J Neuroinflammation 21(1):3 |
| abstractText | 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 alpha7 nicotinic acetylcholine receptor (alpha7nAChR) on macrophages plays a key role in mediating cholinergic anti-inflammatory effects through a downstream intracellular mechanism involving inhibition of NF-kappaB signaling, which results in suppression of pro-inflammatory cytokine production. However, the role of the alpha7nAChR 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 alpha7nAChR-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 alpha7nAChR-deficient monocytes adoptively transferred to WT mice showed significantly diminished recruitment to the inflamed tissue. alpha7nAChR 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, beta1 and beta2 integrins) and chemokine receptors (CCR2 and CCR5) revealed reduced expression of integrin alphaM and alphaX on alpha7nAChR-deficient macrophages. Decreased expression of alphaMbeta2 was confirmed on fluorescently labeled, adoptively transferred alpha7nAChR-deficient macrophages in the lungs of endotoxemic mice, indicating a potential mechanism for alpha7nAChR-mediated migration. CONCLUSIONS: We demonstrate a novel role for the alpha7nAChR in mediating macrophage recruitment to inflamed tissue, which indicates an important new aspect of the cholinergic regulation of immune responses and inflammation. |
