Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke

Abstract

Neuroinflammation is initiated in response to ischemic stroke, generally with the hallmarks of microglial activation and collateral brain injury contributed by robust inflammatory effects. Triggering receptor expressed on myeloid cells (TREM)-1, an amplifier of the innate immune response, is a critical regulator of inflammation. This study identified that microglial TREM-1 expression was upregulated following cerebral ischemic injury. After pharmacologic inhibition of TREM-1 with synthetic peptide LP17, ischemia-induced infarction and neuronal injury were substantially alleviated. Moreover, blockade of TREM-1 can potentiate cellular proliferation and synaptic plasticity in hippocampus, resulting in long-term functional improvement. Microglial M1 polarization and neutrophil recruitment were remarkably abrogated as mRNA levels of M1 markers, chemokines, and protein levels of myeloperoxidase and intracellular adhesion molecule-1 (ICAM-1) were decreased by LP17. Mechanistically, both in vivo and in vitro, we delineated that TREM-1 can activate downstream pro-inflammatory pathways, CARD9/NF-κB, and NLRP3/caspase-1, through interacting with spleen tyrosine kinase (SYK). In addition, TREM-1-induced SYK initiation was responsible for microglial pyroptosis by elevating levels of gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), and forming GSDMD pores, which can facilitate the release of intracellular inflammatory factors, in microglia. In summary, microglial TREM-1 receptor yielded post-stroke neuroinflammatory damage via associating with SYK.

Programmed Cell Deaths and Potential Crosstalk With Blood–Brain Barrier Dysfunction After Hemorrhagic Stroke

“…The Ac-YVAD-CMK administration reduced M1-type microglia polarization and increased the number of M2-type cells around the hematoma (Lin et al, 2018). This characteristic polarization of microglia was also reported to reduce the poststroke neuroinflammatory damage in an ischemic stroke study (Xu et al, 2019).…”

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

“…Quantitative real-time PCR was conducted as previously described [9]. Total RNA was extracted from left cortical tissue or cultured BV2 cells using TRIzol reagent (Invitrogen, USA) and quantified by NanoDrop (Thermo Fisher, USA).…”

“…The activated microglia can be transformed into two different phenotypes (M1 and M2) with distinct physiological functions in responses to different stimulators [8]. M1 microglia, which are usually activated by immune receptors including toll-like receptors (TLRs), and nucleotide-binding oligomerization domains (NODs), can recognize and respond to pathogens by secreting proinflammatory cytokines and chemokines (such as IL-1β and TNFα), ultimately elevating the immune response and exacerbating brain damage [9,10]. In contrast to the proinflammatory M1 phenotype, M2 microglia have been proved to mediate neuroprotective effects via producing anti-inflammatory cytokines such as IL-10 and promoting tissue repair and angiogenesis [11,12].…”

Exogenous hydrogen sulfide alleviates surgery-induced neuroinflammatory cognitive impairment in adult mice by inhibiting NO signaling

“…Besides, oxidative stress could mediate inflammation and apoptosis in hippocampus, which promote hippocampal lesions [39]. Importantly, microglial activation is a hallmark of the onset of neuroinflammation, and contributes to collateral brain injury [40]. Microglial activation plays a pivotal pathogenic role in the initiation of cognitive disorder-related illness, such as AD [41].…”