Activation of α7 nicotinic acetylcholine receptor protects M2 macrophages from ER stress‐induced apoptosis

Abstract

The α7 nicotinic acetylcholine receptor (α7nAChR) is expressed in many non‐neuronal cell types including immune cells, and is now recognized to be involved in a variety of inflammatory events. Atherosclerosis is a chronic inflammatory disease of the vascular wall, and macrophages (MΦ) are essential contributors to the development of atherosclerotic lesions. MΦ apoptosis and inefficient efferocytosis are associated with necrotic core formation and lesion destabilization. MΦs express α7nAChR but the potential role of α7nAChR in MΦ survival and apoptosis has yet to be explored. In bone marrow‐derived MΦs (BMDMs) which were polarized to pro‐inflammatory “M1” or anti‐inflammatory “M2” phenotypes, nicotine exerted a protective action against ER stress‐induced apoptosis in M2 but not M1 MΦs; this effect was lost in α7KO M2 MΦs. Concomitantly, nicotine treatment resulted in increased STAT3 phosphorylation which was reduced in the α7KO MΦs, and abrogated upon inhibition of the upstream regulator JAK2. Our results suggest that activation of the α7nAChR protects M2 MΦs from apoptosis, presumably through regulation of survival genes through activation of the JAK2/STAT3 pathway. Supported by R01HL111877–01.