TREM2 modulates neuroinflammation with elevated IRAK3 expression and plays a neuroprotective role after experimental SAH in rats

Cheng Cao; Jiasheng Ding; Demao Cao; Bing Li; Jiang Wu; Xiang Li; Haiying Li; Gang Cui; Haitao Shen; Gang Chen

doi:10.1016/j.nbd.2022.105809

TREM2 modulates neuroinflammation with elevated IRAK3 expression and plays a neuroprotective role after experimental SAH in rats

Neurobiol Dis. 2022 Sep:171:105809. doi: 10.1016/j.nbd.2022.105809. Epub 2022 Jul 1.

Authors

Cheng Cao¹, Jiasheng Ding², Demao Cao², Bing Li², Jiang Wu², Xiang Li², Haiying Li², Gang Cui³, Haitao Shen⁴, Gang Chen²

Affiliations

¹ Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China; Department of Neurocritical Intensive Care Unit, The Affiliated Jiangyin Hospital, School of Medicine, Southeast University, Jiangyin City 214400, Jiangsu Province, China.
² Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China.
³ Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China. Electronic address: 2445133252@qq.com.
⁴ Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China. Electronic address: dagezi120@126.com.

PMID: 35781003
DOI: 10.1016/j.nbd.2022.105809

Abstract

Background: The modulation of neuroinflammation is a new direction that may alleviate the early brain injury after subarachnoid hemorrhage (SAH). Brain resident microglia/macrophages (Mi/MΦ) are the key drivers of neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to play a neuroprotective role by activating phagocytosis and suspending inflammatory response in experimental ischemic stroke and intracerebral hemorrhage. This study was designed to investigate the role of TREM2 on neuroinflammation and neuroprotective effects in a rat SAH model.

Methods: Adult male Sprague-Dawley rats were induced SAH through endovascular perforation. Lentivirus vectors were administered by i.c.v. to induce TREM2 overexpression or knockdown 7 days before SAH induction. Short- and long-term neurobehavioral tests, western blotting, immunofluorescence, enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase dUTP nick end labeling and Nissl staining were performed to explore the neuroprotective role of TREM2 after SAH.

Results: The expression of TREM2 elevated in a rat SAH model with a peak at 48 h after SAH and mainly expressed in Mi/MΦ in brain. TREM2 overexpression improved short- and long-term neurological deficits induced by SAH in rats, while TREM2 knockdown worsened neurological dysfunction. The rats with TREM2 overexpressed presented less neuronal apoptosis and more neuronal survival at 48 h after SAH, while the rats with TREM2 knockdown presented on the contrary. TREM2 overexpression manifested activated phagocytosis and suppressed inflammatory response, with the increase of CD206⁺/CD11b⁺ cells and IL-10 expression as well as the decrease of the infiltration of MPO⁺ cells and the expression of TNF-α, IL-1β. While TREM2 knockdown abolished these effects. The protein level of IRAK3, a negative regulatory factor of inflammation, was significantly elevated after TREM2 overexpression and declined after TREM2 knockdown.

Conclusions: Our research suggested TREM2 played a neuroprotective role and improved the short- and long-term neurological deficits by modulating neuroinflammation after SAH. The modulation on neuroinflammation of TREM2 after SAH was related with the elevated protein level of IRAK3.

Keywords: IRAK3; Microglia/macrophages; Neuroinflammation; Subarachnoid hemorrhage; TREM2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Male
Neuroinflammatory Diseases
Neuroprotection
Neuroprotective Agents* / pharmacology
Rats
Rats, Sprague-Dawley
Signal Transduction / physiology
Subarachnoid Hemorrhage* / metabolism

Substances

Neuroprotective Agents