Resident Microglia Activate before Peripheral Monocyte Infiltration and p75NTR Blockade Reduces Microglial Activation and Early Brain Injury after Subarachnoid Hemorrhage

Abstract

Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (SAH) contributes to high morbidity and mortality. Although it is well recognized that acute neuroinflammation reaction is one of the most important triggers of EBI, pharmacotherapy proved to be clinically effective against the initiating of neuroinflammation after SAH is lacking. The resident microglia and infiltrated peripheral monocyte are two main types of immune cells in central nervous system (CNS) and control the inflammation process in brain after SAH. But the time course and relative contributions of these two immune cell activations after SAH are unknown. The p75 neurotrophin receptor (p75NTR), member of TNF receptor superfamily, expresses on infiltrated peripheral monocytes and suppresses their proinflammatory action after brain insults. But the p75NTR expression on resident microglia in vivo is rarely explored and their function keeps elusive. Therefore, we designed this study to investigate the time course of resident microglia activation and peripheral monocyte infiltration, as well as the microglial expression of p75NTR by using CX3C-chemokine receptor 1 (Cx3cr1) and chemokine receptor 2 (Ccr2) double transgenic mice (Cx3cr1Ccr2) after SAH. The results showed activated microglia was observed in cortex as early as 24 h and further increased at 48 and 72 h post SAH, while the infiltrated monocyte was not found until 72h. In addition, activated microglia expressed p75NTR acutely and p75NTR specific antagonist TAT-Pep5 significantly reduced microglia activation, neuroinflammation and EBI from 24 to 72 h. Together, these data suggest that the early neuroinflammation reaction might be initiated and intensified mainly by resident microglia rather than infiltrated monocyte at least in the first 48 h after SAH and p75NTR blockading by TAT-Pep5P might alleviate EBI through mediating microglial activation.

Soluble ST2 links inflammation to outcome after subarachnoid hemorrhage

“…Consistent with this, we found that aneurysm rupture and high levels of sST2 after rupture were associated with shifts in immune cell populations. Our comparison between SAH patients and control patients undergoing elective aneurysm clipping found an apparent shift in a CD14 + monocyte population, which is consistent with animal studies of SAH . Human studies have similarly shown increases in monocyte‐associated genes after aneurysm rupture, elevations in monocyte chemoattractant protein 1 in serum and CSF after SAH, and increase in activated monocytes identified by CSF and peripheral blood flow cytometry .…”

Heat-Shock Proteins in Neuroinflammation

“…Brain-resident microglia cells are the first responders to central nervous system (CNS) damage; they accumulate within a short period of time in the injured area and begin the phagocytic removal of myelin debris, which is important because this debris can release axonal regrowth–inhibiting factors. Moreover, activated microglia also play an important role in glial scar formation and in support of the blood–brain barrier (BBB) (Mosley and Cuzner, 1996; Schwab, 2004; Davalos et al, 2005; Lou et al, 2016; Xu et al, 2019). However, through their TLRs, DAMPs activate the pro-inflammatory phenotype of microglia besides the early phagocytic phenotype, which is destructive to the brain tissue since it can produce pro-inflammatory cytokines, chemokines, complement system components, free radicals, and matrix metalloproteases (MMPs) which could result in an increase in BBB permeability and apoptosis (Walker et al, 1995; Jack et al, 2005; Yenari et al, 2006; del Zoppo et al, 2012; Kawabori and Yenari, 2015).…”

Resolvin D1 ameliorates Inflammation-Mediated Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in rats by Modulating A20 and NLRP3 Inflammasome

“…Microglia and neutrophils are key immune cells involved in the inflammatory response in CNS inflammation-related diseases, such as hypoxicischemic brain injury and SAH (Z. Xu et al, 2019b;Yao and Kuan, 2020). FPR2, a member of the G protein-coupled receptor family, plays an important role in host defense and cellular debris clearance (Weiss and Kretschmer, 2018).…”