Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke

Zhang, Gufang; Li, Qi; Tao, Weijie; Qin, Pingping; Chen, Jiali; Yang, Huicui; Chen, Jiaojiao; Liu, Hua; Dai, Qijun; Zhen, Xuechu

doi:10.7150/thno.77088

Nanotheranostics 2025; 9(1): 52-62. Full text PDF

Nanotheranostics 2025; 9(1): 38-51. Full text PDF PubMed PMC

Nanotheranostics

International Journal of Biological Sciences

International Journal of Medical Sciences

Journal of Cancer

open access Global reach, higher impact

Full Text | PDF

Theranostics 2023; 13(2):543-559. doi:10.7150/thno.77088 This issue Cite

Research Paper

Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke

Gufang Zhang¹, Qi Li¹, Weijie Tao¹, Pingping Qin¹, Jiali Chen¹, Huicui Yang¹, Jiaojiao Chen¹, Hua Liu², Qijun Dai^2✉, Xuechu Zhen^1✉

1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
2. Department of Neurobiology, Hai'an Hospital of Traditional Chinese Medicine, Hai'an 226600, China.

Citation:

Zhang G, Li Q, Tao W, Qin P, Chen J, Yang H, Chen J, Liu H, Dai Q, Zhen X. Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke. Theranostics 2023; 13(2):543-559. doi:10.7150/thno.77088. https://www.thno.org/v13p0543.htm

Other styles

Abstract

Background: Efferocytosis of apoptotic neurons by macrophages is essential for the resolution of inflammation and for neuronal protection from secondary damage. It is known that alteration of the Sigma-1 receptor (Sig-1R) is involved in the pathological development of some neurological diseases, including ischemic stroke. The present study aimed to investigate whether and how Sig-1R regulates the phagocytic activity of macrophages/microglia and its significance in neuroprotection and neurological function in stroke.

Methods: The roles of Sig-1R in the efferocytosis activity of microglia/macrophages using bone marrow-derived macrophages (BMDMs) or using Sig-1R knockout mice subjected to transient middle artery occlusion (tMCAO)-induced stroke were investigated. The molecular mechanism of Sig-1R in the regulation of efferocytosis was also explored. Adoptive transfer of Sig-1R intact macrophages to recipient Sig-1R knockout mice with tMCAO was developed to observe its effect on apoptotic neuron clearance and stroke outcomes.

Results: Depletion of Sig-1R greatly impaired the phagocytic activity of macrophages/microglia, accordingly with worsened brain damage and neurological defects in Sig-1R knockout mice subjected to tMCAO. Adoptive transfer of Sig-1R intact bone marrow-derived macrophages (BMDMs) to Sig-1R knockout mice restored the clearance activity of dead/dying neurons, reduced infarct area and neuroinflammation, and improved long-term functional recovery after cerebral ischemia. Mechanistically, Sig-1R-mediated efferocytosis was dependent on Rac1 activation in macrophages, and a few key sites of Rac1 in its binding pocket responsible for the interaction with Sig-1R were identified.

Conclusion: Our data provide the first evidence of the pivotal role of Sig-1R in macrophage/microglia-mediated efferocytosis and elucidate a novel mechanism for the neuroprotection of Sig-1R in ischemic stroke.

Keywords: Ischemic stroke, Efferocytosis, Macrophage/microglia, Sigma-1 receptor, Rac1

Citation styles

APA

Zhang, G., Li, Q., Tao, W., Qin, P., Chen, J., Yang, H., Chen, J., Liu, H., Dai, Q., Zhen, X. (2023). Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke. Theranostics, 13(2), 543-559. https://doi.org/10.7150/thno.77088.

ACS

Zhang, G.; Li, Q.; Tao, W.; Qin, P.; Chen, J.; Yang, H.; Chen, J.; Liu, H.; Dai, Q.; Zhen, X. Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke. Theranostics 2023, 13 (2), 543-559. DOI: 10.7150/thno.77088.

NLM

CSE

Zhang G, Li Q, Tao W, Qin P, Chen J, Yang H, Chen J, Liu H, Dai Q, Zhen X. 2023. Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke. Theranostics. 13(2):543-559.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.