PMID- 36632219
OWN - NLM
STAT- MEDLINE
DCOM- 20230215
LR  - 20231213
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 13
IP  - 2
DP  - 2023
TI  - Sigma-1 receptor-regulated efferocytosis by infiltrating circulating 
      macrophages/microglial cells protects against neuronal impairments and promotes 
      functional recovery in cerebral ischemic stroke.
PG  - 543-559
LID - 10.7150/thno.77088 [doi]
AB  - 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.
CI  - (c) The author(s).
FAU - Zhang, Gufang
AU  - Zhang G
AD  - Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of 
      Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 
      Jiangsu 215123, China.
FAU - Li, Qi
AU  - Li Q
AD  - Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of 
      Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 
      Jiangsu 215123, China.
FAU - Tao, Weijie
AU  - Tao W
AD  - Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of 
      Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 
      Jiangsu 215123, China.
FAU - Qin, Pingping
AU  - Qin P
AD  - Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of 
      Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 
      Jiangsu 215123, China.
FAU - Chen, Jiali
AU  - Chen J
AD  - Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of 
      Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 
      Jiangsu 215123, China.
FAU - Yang, Huicui
AU  - Yang H
AD  - Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of 
      Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 
      Jiangsu 215123, China.
FAU - Chen, Jiaojiao
AU  - Chen J
AD  - Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of 
      Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 
      Jiangsu 215123, China.
FAU - Liu, Hua
AU  - Liu H
AD  - Department of Neurobiology, Hai'an Hospital of Traditional Chinese Medicine, 
      Hai'an 226600, China.
FAU - Dai, Qijun
AU  - Dai Q
AD  - Department of Neurobiology, Hai'an Hospital of Traditional Chinese Medicine, 
      Hai'an 226600, China.
FAU - Zhen, Xuechu
AU  - Zhen X
AD  - Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of 
      Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 
      Jiangsu 215123, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230101
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Ischemic Stroke/pathology
MH  - Macrophages/metabolism
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microglia/metabolism
MH  - Neurons/pathology
MH  - *Apoptosis
MH  - *Neuroprotection
MH  - Sigma-1 Receptor
PMC - PMC9830433
OTO - NOTNLM
OT  - Efferocytosis
OT  - Ischemic stroke
OT  - Macrophage/microglia
OT  - Rac1
OT  - Sigma-1 receptor
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2023/01/13 06:00
MHDA- 2023/01/14 06:00
PMCR- 2023/01/01
CRDT- 2023/01/12 01:56
PHST- 2022/07/13 00:00 [received]
PHST- 2022/12/05 00:00 [accepted]
PHST- 2023/01/12 01:56 [entrez]
PHST- 2023/01/13 06:00 [pubmed]
PHST- 2023/01/14 06:00 [medline]
PHST- 2023/01/01 00:00 [pmc-release]
AID - thnov13p0543 [pii]
AID - 10.7150/thno.77088 [doi]
PST - epublish
SO  - Theranostics. 2023 Jan 1;13(2):543-559. doi: 10.7150/thno.77088. eCollection 
      2023.