Biglycan regulates neuroinflammation by promoting M1 microglial activation in early brain injury after experimental subarachnoid hemorrhage

Abstract

Neuroinflammation can be caused by various factors in early brain injury after subarachnoid hemorrhage (SAH). One of the most important features of this process is M1 microglial activation. In turn, the TLR4/NF-κB pathway plays an essential role in activating M1 phenotypic microglia. Biglycan, a small leucine-rich proteoglycan, functions as an endogenous ligand of TLR4 and TLR2 in macrophages. However, the underlying mechanisms associated with microglial activation in stroke pathogenesis are poorly understood. Here, we aimed to identify the role of biglycan in neuroinflammation following SAH. In our study, SAH was induced by endovascular perforation in young male C57BL/6J mice. Lentiviral vector was administered intracerebroventricularly to knock down Biglycan. Post-SAH assessments included neurobehavioral tests, immunofluorescence, western blot, qRT-PCR, Co-IP, flow cytometry, and ELISA. The biglycan level was markedly elevated following SAH in vivo. Of particularly note, knockdown of biglycan significantly improved neurological outcomes.TLR4 was bound with soluble biglycan in vitro. In addition, biglycan down-regulation suppressed the expression of phosphorylated-NF-κB p65 (p-NF-κB) and inducible nitric oxide synthase (iNOS), as well as the cytokine (TNF-α, IL-1β, and IL-6) production in vivo and in vitro. Moreover, we detected a decreased expression of CD16/32 and CD86, M1 markers when biglycan was inhibited in vitro. Our work suggests that biglycan can induce neuroinflammation by promoting M1 microglial activation at least in part through TLR4/NF-κB signaling pathway after experimental SAH. Targeting biglycan may be a promising strategy for the clinical management of SAH. K E Y W O R D Sbiglycan, early brain injury, microglia, neuroinflammation, subarachnoid hemorrhage, TLR4 | 369 XIE Et al.

α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia

“…Alternatively, it may be that endogenous ligands of Toll‐like receptor 4 (TLR4), the receptor to which LPS binds to exert its downstream signaling effects, serve to prime microglia for subsequent activation by α‐syn in vivo. High mobility group box 1 (HMGB1), biglycan, and heat shock protein 70 (Hsp70) all have been identified as endogenous TLR4 ligands in the brain (Gou et al, 2020; Martín‐Hernández et al, 2018; Xie et al, 2020).…”

MiR-26b-5p-modified hUB-MSCs derived exosomes attenuate early brain injury during subarachnoid hemorrhage via MAT2A-mediated the p38 MAPK/STAT3 signaling pathway

“…Numerous studies have shown that neuroin ammation and blood-brain barrier disruption are the two main pathological mechanisms of early brain injury after SAH [21]. After SAH, blood rapidly enters the subarachnoid space, resulting in increased intracranial pressure, decreased cerebral blood ow, and transient cerebral ischemia.…”

Ponesimod protects against neuronal death by suppressing the activation of A1 astrocytes in early brain injury after experimental subarachnoid hemorrhage

“…The neurological performances were evaluated at 48 hr after SAH by a blinded investigator using the modified Garcia score system and beam balance test as previously described (Xie et al., 2019). The modified Garcia test (maximum score = 18) included spontaneous activity (scores 0–3), spontaneous movement of the four limbs (scores 0–3), forelimbs outstretching (scores 0–3), climbing capacity (scores 1–3), trunk touch (scores 1–3), and vibrissa touch (scores 1–3).…”