LDC7559 Exerts Neuroprotective Effects by Inhibiting GSDMD-Dependent Pyroptosis of Microglia in Mice with Traumatic Brain Injury

Yu, Enxing; zhang, erjia; Lv, Xinhuang; Yang, Lin; Lin, Zhongxiao; Siaw-Debrah, Felix; Zhang, Ying; Yang, Shuxu; Ruan, Linhui; Zhuge, Qichuan; Ni, Haoqi

doi:10.1089/neu.2021.0318

Cited by 7 publications

(9 citation statements)

References 63 publications

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“…According to previous studies, LDC7559 has been verified as a selective pyroptosis inhibitor ( 21 ). In models of TBI, LDC7559 significantly inhibited GSDMD and cleaved GSDMD in microglia.…”

Section: Discussionmentioning

confidence: 91%

“…Microglial activation is essential to neuroinflammation after SAH. A previous study reported that LDC7559 can inhibit microglial proliferation and activation after TBI ( 21 ). In time, the pro-inflammatory cytokines release after TBI were decreased by LDC7559.…”

Section: Resultsmentioning

confidence: 99%

“…In models of TBI, LDC7559 significantly inhibited GSDMD and cleaved GSDMD in microglia. Meanwhile, LDC7559 improved neurobehavioral function and mitigated brain tissue loss after TBI ( 21 ). Consistent with previous reports, our data indicated that LDC7559 dramatically inhibited microglial activation and the pro-inflammatory cytokines release after SAH.…”

Section: Discussionmentioning

confidence: 99%

“…Nigericin (5 µM) was added into culture medium after Hb stimulation. The concentrations and administration routes of LDC7559 and nigericin were based on previous studies ( 21 , 24 ).…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have indicated that LDC7559 could block the GSDMD-N domain, thereby suppressing inflammation (19,20). A recent study by Yu et al reported that LDC7559 can suppress pyroptosis and inhibit neuroinflammation by suppressing GSDMD after traumatic brain injury (TBI) both in vivo and in vitro (21). However, the potential role of LDC7559 in SAH remains unknown.…”

mentioning

confidence: 99%

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LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage

Cai¹,

Lai

et al. 2023

Front. Immunol.

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Mounting evidence indicates that inhibition of microglial activation and neuronal pyroptosis plays important roles in brain function recovery after subarachnoid hemorrhage (SAH). LDC7559 is a newly discovered gasdermin D (GSDMD) inhibitor. Previous studies have demonstrated that LDC7559 could inhibit microglial proliferation and pyroptosis. However, the beneficial effects of LDC7559 on SAH remain obscure. Based on this background, we investigated the potential role and the mechanism of LDC7559 on SAH-induced brain damage both in vivo and in vitro. The findings revealed that microglial activation and neuronal pyroptosis were evidently increased after SAH, which could be markedly suppressed by LDC7559 both in vivo and in vitro. Meanwhile, LDC7559 treatment reduced neuronal apoptosis and improved behavior function. Mechanistically, LDC7559 decreased the levels of GSDMD and cleaved GSDMD after SAH. In contrast, nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation by nigericin increased GSDMD-mediated pyroptosis and abated the beneficial effects of LDC7559 on SAH-induced brain damage. However, LDC7559 treatment did not significantly affect the expression of NLRP3 after SAH. Taken together, LDC7559 might suppress neuronal pyroptosis and microglial activation after SAH by inhibiting GSDMD, thereby promoting brain functional recovery.

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Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Nigericin (5 µM) was added into culture medium after Hb stimulation. The concentrations and administration routes of LDC7559 and nigericin were based on previous studies ( 21 , 24 ).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage

Cai¹,

Lai

et al. 2023

Front. Immunol.

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Role of NLRP3 inflammasome-mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases

Han,

Liu,

Jin

et al. 2023

Inflamm. Res.

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Hepatic HRC induces hepatocyte pyroptosis and HSCs activation via NLRP3/caspase-1 pathway

Zhang

Xia

et al. 2022

J Mol Med

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The histidine-rich calcium-binding protein (HRC) is a regulator of Ca2 + homeostasis and it plays a signi cant role in liver brosis. Pyroptosis, a speci c in ammatory cell death, can lead to HSCs activation and liver brosis. However, the role of HRC in pyroptosis has not been explored. In this study, we demonstrated that HRC, mainly located in the hepatocyte, was overexpressed in brotic liver tissues. We further found that enforced expression of HRC in hepatocytes induced pyroptosis and HMGB1 release, and subsequently led to HSCs activation by NLRP3/caspase-1 pathway. In addition, the proliferation and migration of HSCs were also enhanced by HRC overexpression in hepatocytes. Furthermore, NLRP3 inhibitor MCC950 and caspase-1 inhibitor VX-765 alleviated hepatic HRC-mediated hepatocytes pyroptosis and HSCs activation. This study demonstrated that hepatic HRC promoted HSCs activation by inducing hepatocyte pyroptosis, which suggests HRC may be a promising therapeutic target to prevent liver brosis.

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LDC7559 Exerts Neuroprotective Effects by Inhibiting GSDMD-Dependent Pyroptosis of Microglia in Mice with Traumatic Brain Injury

Cited by 7 publications

References 63 publications

LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage

LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage

Role of NLRP3 inflammasome-mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases

Hepatic HRC induces hepatocyte pyroptosis and HSCs activation via NLRP3/caspase-1 pathway

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