Abstract
The α7 nicotinic acetylcholine receptor (nAChR) is widely distributed in the central and peripheral nervous systems and is closely related to a variety of nervous system diseases and inflammatory responses. The α7 nAChR subtype plays a vital role in the cholinergic anti-inflammatory pathway. In vivo, ACh released from nerve endings stimulates α7 nAChR on macrophages to regulate the NF-κB and JAK2/STAT3 signaling pathways, thereby inhibiting the production and release of downstream proinflammatory cytokines and chemokines. Despite a considerable level of recent research on α7 nAChR-mediated immune responses, much is still unknown. In this study, we used an agonist (PNU282987) and antagonists (MLA and α-conotoxin [A10L]PnIA) of α7 nAChR as pharmacological tools to identify the molecular mechanism of the α7 nAChR-mediated cholinergic anti-inflammatory pathway in RAW264.7 mouse macrophages. The results of quantitative PCR, ELISAs, and transcriptome analysis were combined to clarify the function of α7 nAChR regulation in the inflammatory response. Our findings indicate that the agonist PNU282987 significantly reduced the expression of the IL-6 gene and protein in inflammatory macrophages to attenuate the inflammatory response, but the antagonists MLA and α-conotoxin [A10L]PnIA had the opposite effects. Neither the agonist nor antagonists of α7 nAChR changed the expression level of the α7 nAChR subunit gene; they only regulated receptor function. This study provides a reference and scientific basis for the discovery of novel α7 nAChR agonists and their anti-inflammatory applications in the future.
Highlights
Nicotinic acetylcholine receptors are ligand-gated ion channel proteins regulated by acetylcholine (ACh) and are widely distributed in muscles and the central and peripheral nervous systems. nicotinic acetylcholine receptor (nAChR) consist of five transmembrane subunits, and 12 neuronal nAChR subunits have been cloned, including nine α subunits (α2–α10) and three β subunits (β2–β4) [1–3]. α7 nAChR, an important homopentamer, is widely distributed in the mammalian central nervous system (CNS), including the cerebral cortex, olfactory bulb, and hippocampus
This study investigated whether the regulation of inflammation by agonist and antagonists is related to the expression of α7 nAChR (Figure 7). quantitative PCR (qPCR) results showed that the α7 nAChR agonist PNU282987 exerted no significant effect on α7 nAChR gene expression levels in normal and inflammatory RAW264.7 cells
This study showed that the differentially expressed genes induced by the α7 nAChR
Summary
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channel proteins regulated by acetylcholine (ACh) and are widely distributed in muscles and the central and peripheral nervous systems. nAChRs consist of five transmembrane subunits, and 12 neuronal nAChR subunits have been cloned, including nine α subunits (α2–α10) and three β subunits (β2–β4) [1–3]. α7 nAChR, an important homopentamer, is widely distributed in the mammalian central nervous system (CNS), including the cerebral cortex, olfactory bulb, and hippocampus. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channel proteins regulated by acetylcholine (ACh) and are widely distributed in muscles and the central and peripheral nervous systems. Α7 nAChR is expressed on peripheral cells such as macrophages, lung cancer cells, cardiomyocytes, and vascular endothelial cells and is a key protein in the cholinergic anti-inflammatory pathway [8–12]. Previous studies have shown that the cholinergic anti-inflammatory pathway regulated by α7 nAChR is a key pathway for the treatment of pneumonia and that α7 nAChR can affect the proliferation, angiogenesis, metastasis, and apoptosis of lung cancer cells, gastric cancer cells, colon cancer cells, and other malignant tumor cells [15–17]. An in-depth study on the role and mechanism of α7 nAChR in the cholinergic anti-inflammatory pathway is an important basis for the design of α7 nAChR-related anti-inflammatory drugs
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