TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice

Abstract

Background Neuroinflammation is an important host defense response to secondary brain injury after intracerebral hemorrhage (ICH). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects by attenuating neuroinflammation in experimental ischemic stroke. Recent studies suggest that apolipoprotein E (apoE) is a novel, high-affinity ligand of TREM2. This study aimed to investigate the effects of TREM2 activation on neuroinflammation and neuronal apoptosis in a mouse model of ICH. Methods Adult male CD1 mice (n = 216) were subjected to intrastriatal injection of bacterial collagenase. The TREM2 ligand, apoE-mimetic peptide COG1410 was administered intranasally at 1 h after ICH induction. To elucidate the underlying mechanism, TREM2 small interfering RNA (siRNA) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were administered intracerebroventricularly prior to COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, western blotting, and Fluoro-Jade C- and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. Results Endogenous TREM2 expression was increased and peaked at 24 h after ICH. TREM2 was expressed on microglia, astrocytes, and neurons. COG1410 improved both short-term and long-term neurological functions, reduced brain edema, inhibited microglia/macrophage activation and neutrophil infiltration, and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Knockdown of endogenous TREM2 by TREM2 siRNA aggravated neurological deficits and decreased the expression of TREM2 in naïve and ICH mice. COG1410 was associated with upregulation of TREM2, PI3K, phosphorylated-Akt, and Bcl-2 and downregulation of TNF-α, IL-1β, and Bax after ICH. The neuroprotective effects of COG1410 were abolished by both TREM2 siRNA and PI3K inhibitor LY294002. Conclusions Our finding demonstrated that TREM2 activation improved neurological functions and attenuated neuroinflammation and neuronal apoptosis after ICH, which was, at least in part, mediated by activation of PI3K/Akt signaling pathway. Therefore, activation of TREM2 may be a potential therapeutic strategy for the management of ICH patients.

Recombinant CCL17-dependent CCR4 activation alleviates neuroinflammation and neuronal apoptosis through the PI3K/AKT/Foxo1 signaling pathway after ICH in mice

“…This response after ICH may involve, at least in part, activation of the PI3K/AKT/Foxo1 signaling pathway through CCR4. Our findings are consistent with those of previous studies [ 45 , 47 ].…”

“…Multiple studies have suggested that the inflammatory cascade following ICH plays a vital role in exacerbating the mass effect of hematoma, accelerating perihematomal edema, promoting neuronal apoptosis, and worsening the neurological outcome after ICH [ 44 ]. Additionally, activation of microglia/macrophages and infiltration of neutrophils post-ICH injury may further facilitate the production of proinflammatory cytokines and neuronal apoptotic pathways, which in turn lead to neuroinflammation and neuronal apoptosis [ 45 ]. Consistent with previous studies [ 8 ], our study found that rCCL17 therapy attenuated neurological deficits and decreased BWC at 72 h post-ICH.…”

Targeting neuroprotective functions of astrocytes in neuroimmune diseases

“…Even though microglia are the main cell type of the brain expressing TREM2, it has also been detected in both murine and human astrocytes. Overexpression of TREM2 has beneficial effects in several animal models of neurodegenerative diseases, including AD, PD and multiple sclerosis [15,26]. Rosciszewski et al [27] demonstrate TLR4-dependent proinflammatory activation of murine astrocytes, measured as nuclear factor (NF)-κB activation and increased secretion of IL-1β and TNF; stimulating astrocyte TREM2 suppresses this activation.…”

Role of Ginkgolides in the Inflammatory Immune Response of Neurological Diseases: A Review of Current Literatures

“…Numerous studies have proven that neuroinflammation plays an important pathological role in ischemic stroke (Chen et al, 2020 ). Extracellular glutamate increased significantly after ischemia (Hsieh et al, 2017 ).…”