TREM1 Regulates Neuroinflammatory Injury by Modulate Proinflammatory Subtype Transition of Microglia and Formation of Neutrophil Extracellular Traps via Interaction With SYK in Experimental Subarachnoid Hemorrhage.

Xinyan Wu,Yucong Peng,Huaijun Chen,Hanhai Zeng,Linfeng Fan,Hang Zhou,Qian Yu,Feng Yan,Xiongjie Fu,Chaoran Xu,Xiaobo Yu,Gao Chen

doi:10.3389/fimmu.2021.766178

Abstract

Neuroinflammation is a key process in the pathogenesis of subarachnoid hemorrhage (SAH) and contributes to poor outcome in patients. The purpose of this study is to explore the effect of triggering receptor expressed on myeloid cells 1 (TREM1) in the SAH, as well as its potential mechanism. In our study, plasma levels of soluble TREM1 was increased significantly after SAH and correlated to SAH severity and serum C-reactiveprotein. TREM1 inhibitory peptide LP17 alleviated the neurological deficits, attenuated brain water content, and reduced neuronal damage after SAH. Meanwhile, TREM1 inhibitory peptide decreased neuroinflammation (evidenced by the decreased levels of markers including IL-6, IL-1β, TNF-α) by attenuating proinflammatory subtype transition of microglia (evidenced by the decreased levels of markers including CD68, CD16, CD86) and decreasing the formation of neutrophil extracellular traps (evidenced by the decreased levels of markers including CitH3, MPO, and NE). Further mechanistic study identified that TREM1 can activate downstream proinflammatory pathways through interacting with spleen tyrosine kinase (SYK). In conclusion, inhibition of TREM1 alleviates neuroinflammation by attenuating proinflammatory subtype transition of microglia and decreasing the formation of neutrophil extracellular traps through interacting with SYK after SAH. TREM1 may be a a promising therapeutic target for SAH.

Highlights

Subarachnoid hemorrhage (SAH) is a major cause of devastating outcomes after neurosurgery practice, leading to severe neurological deficits for survivors [1, 2]
We studied the effectiveness of triggering receptor expressed on myeloid cells 1 (TREM1) inhibitory peptide LP17 on neurological damage evaluated by the modified Garcia and beam balance test and brain water content at 24 h after subarachnoid hemorrhage (SAH)
TREM1 has been reported to be a potential target for treating brain injury in central nervous system (CNS) disease including SAH [9, 36, 37], but no study has focused on the role of TREM1 in proinflammatory subtype transition of microglia and formation of Neutrophil extracellular traps (NETs) following SAH

Summary

Introduction

Subarachnoid hemorrhage (SAH) is a major cause of devastating outcomes after neurosurgery practice, leading to severe neurological deficits for survivors [1, 2]. Can detect and respond to invading pathogens through secreting proinflammatory cytokines and chemokines (including IL-6, IL1b, TNF-a), magnifying the immune response and resulting in the exacerbation of brain damage [15, 16] These suggests that successful inhibition of neuroinflammation by suppressing the proinflammatory phenotype microglia could be an promising therapeutic strategy for SAH management. Our previous articles confirmed the role of NETs in SAH and the role of NETs in the induction of proinflammatory subtypes of microglia [17, 19] These suggests that inhibition of neuroinflammation by suppressing the formation of NETs might be an potential therapeutic strategy for SAH management as well

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