Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Abstract

Background Hemorrhagic transformation (HT) is a critical issue in thrombolytic therapy in acute ischemic stroke. Damage-associated molecular pattern (DAMP)-stimulated sterile neuroinflammation plays a crucial role in the development of thrombolysis-associated HT. Our previous study showed that the phthalide derivative CD21 attenuated neuroinflammation and brain injury in rodent models of ischemic stroke. The present study explored the effects and underlying mechanism of action of CD21 on tissue plasminogen activator (tPA)-induced HT in a mouse model of transient middle cerebral artery occlusion (tMCAO) and cultured primary microglial cells. Methods The tMCAO model was induced by 2 h occlusion of the left middle cerebral artery with polylysine-coated sutures in wildtype (WT) mice and macrophage scavenger receptor 1 knockout (MSR1−/−) mice. At the onset of reperfusion, tPA (10 mg/kg) was intravenously administered within 30 min, followed by an intravenous injection of CD21 (13.79 mg/kg/day). Neuropathological changes were detected in mice 3 days after surgery. The effect of CD21 on phagocytosis of the DAMP peroxiredoxin 1 (Prx1) in lysosomes was observed in cultured primary microglial cells from brain tissues of WT and MSR1−/− mice. Results Seventy-two hours after brain ischemia, CD21 significantly attenuated neurobehavioral dysfunction and infarct volume. The tPA-infused group exhibited more severe brain dysfunction and hemorrhage. Compared with tPA alone, combined treatment with tPA and CD21 significantly attenuated ischemic brain injury and hemorrhage. Combined treatment significantly decreased Evans blue extravasation, matrix metalloproteinase 9 expression and activity, extracellular Prx1 content, proinflammatory cytokine mRNA levels, glial cells, and Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway activation and increased the expression of tight junction proteins (zonula occludens-1 and claudin-5), V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, and MSR1. MSR1 knockout significantly abolished the protective effect of CD21 against tPA-induced HT in tMCAO mice. Moreover, the CD21-induced phagocytosis of Prx1 was MSR1-dependent in cultured primary microglial cells from WT and MSR1−/− mice, respectively. Conclusion The phthalide derivative CD21 attenuated tPA-induced HT in acute ischemic stroke by promoting MSR1-induced DAMP (Prx1) clearance and inhibition of the TLR4/NF-κB pathway and neuroinflammation.

Dual-Modality Nanoprobe for Noninvasive Detection of Microthrombus after Cerebral Ischemia/Reperfusion

“…The neurological function of mice was assessed using modified neurological severity score (mNSS, ranging from 0 to 18), , Longa’s neurological deficit score (ranging from 0 to 5), , and Bederson score (ranging from 0 to 4) . These assessments were conducted both before and after CI/R modeling to monitor changes in the mice’s neuro-motor function.…”

Immunomodulatory role of estrogen in ischemic stroke: neuroinflammation and effect of sex

“…These cascade reactions also include cell death-associated damage-associated molecular patterns (DAMP) and subsequent inflammatory responses ( 45 ). DAMPs promote the local activation of microglia and induce the recruitment of leukocytes ( 46 ). In this microenvironment, immune cells secrete pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, which induce local or systemic inflammatory responses ( 46 , 47 ).…”

“…DAMPs promote the local activation of microglia and induce the recruitment of leukocytes ( 46 ). In this microenvironment, immune cells secrete pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, which induce local or systemic inflammatory responses ( 46 , 47 ). Accumulative evidence has revealed that such immune responses can aggravate cerebral ischemic injuries as well as promote nerve regeneration, attenuate inflammation, and improve tissue repair after stroke ( 48 , 49 ).…”

Neutrophils in the brain are sources of neuroprotective molecules and demonstrate functional heterogeneity during chronicToxoplasma gondiiinfection

“…In the liver, MSR1 can activate neutrophil complement responses and worsen hepatitis. However, in the brain, it is more frequently observed in responses to DAMP signaling and can be beneficial during tissue damage [11,[43][44][45]. Indeed, MSR-1-mediated complement activation on neutrophils may have a different connotation within the brain, with synaptic pruning being dependent on the complement pathway.…”