RIP3 dependent NLRP3 inflammasome activation is implicated in acute lung injury in mice

Chen, Jingxian; Wang, Shuang; Fu, Rong; Zhou, Mianjing; Zhang, Tengyue; Pan, Wenxu; Yang, Niansheng; Huang, Yuefang

doi:10.1186/s12967-018-1606-4

Cited by 86 publications

(52 citation statements)

References 20 publications

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“…Studies using high dose oral T. gondii infection have linked excessive Th1 immunity and intestinal pro-inflammatory cell death as the culprit in host mortality (15)(16)(17). The physiological role of RIPK3-dependent necroptosis can drive immunopathology and impair host fitness (35,36,41,42). These findings support the fact that RIPK3 -/mice have improved survival to oral T. gondii infection even with a higher parasite burden (Fig.…”

Section: Discussionsupporting

confidence: 60%

RIPK3 facilitates host and pathogen interactions after oralToxoplasma gondiiinfection

Cervantes

Knoll

2020

Preprint

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Toxoplasma gondii infection activates pattern recognition receptor (PRR) pathways that drive innate inflammatory responses to control infection. Necroptosis is a pro-inflammatory cell death pathway apart of the innate immune response that has evolved to control pathogenic infection. In this study we further defined the role of Z-DNA binding protein 1 (ZBP1) as a PRR and assessed its contribution to necroptosis as a host protection mechanism to T. gondii infection. We found that ZBP1 does not induce pro-inflammatory necroptosis cell death and ZBP1 null mice have reduced survival after oral T. gondii infection. In contrast, mice deleted in receptor-interacting serine/threonine-protein kinase 3 (RIPK3-/-), a central mediator of necroptosis, have significantly improved survival after oral T. gondii infection even with higher parasite burden. The physiological consequences of RIPK3 activity did not show any differences in intestine villi immunopathology but RIPK3-/- mice showed higher immune cell infiltration and edema in the lamina propria. The contribution of necroptosis to host survival was clarified with mixed lineage kinase domain like pseudokinase null (MLKL-/-) mice. We found MLKL-/- mice to succumb to oral T. gondii infection the same as wild type mice, indicating necroptosis-independent RIPK3 activity impacts host survival. These results provide new insights on the impacts of pro-inflammatory cell death pathways as a mechanism of host defense to oral T. gondii infection.

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Section: Discussionsupporting

confidence: 60%

RIPK3 facilitates host and pathogen interactions after oralToxoplasma gondiiinfection

Cervantes

Knoll

2020

Preprint

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“…In THP-1 macrophages subjected to LPS-and ATP-induced NLRP3 inflammasome activation, a novel RIPK3/ NLRP3 complex, leading to caspase-1 activation and IL-1β and IL-18 production, was described. These studies suggest that inflammasome and necroptosis pathways are coregulated in the pathogenesis of lung inflammatory injury (84).…”

Section: Necroptosis-associated Proteins In Pulmonary Diseasementioning

confidence: 92%

Necroptosis: a crucial pathogenic mediator of human disease

et al. 2019

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Conflict of interest: AMKC is a cofounder of, is a stockholder of, and serves on the Scientific Advisory Board for Proterris, Inc., which develops therapeutic uses for carbon monoxide. AMKC also has a use patent (US 7,678,390) on CO. AMKC served as a consultant for Teva Pharmaceuticals in July 2018. The spouse of MEC is a cofounder of, is a shareholder of, and serves on the Scientific Advisory Board of Proterris, Inc.

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“…Previously studies have demonstrated that necroptosis plays essential role in LPS induced ALI and it has been regarded as a promising target for the treatment of lung injury [21,22]. Therefore, we examined whether CO mitigated necroptosis in LPS-induced ALI by qPCR and western blot.…”

Section: Resultsmentioning

confidence: 99%

Carbon Monoxide Attenuates Lipopolysaccharides (LPS)-Induced Acute Lung Injury in Neonatal Rats via Downregulation of Cx43 to Reduce Necroptosis

Wu²,

Chen

et al. 2019

Med Sci Monit

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Background Acute lung injury (ALI) is one of major causes of death in newborns, making it urgent to improve therapy. Administration of low dose carbon monoxide (CO) plays a protective role in ALI but the mechanisms are not fully understood. This study was designed to test the therapeutic effect of monoxide-releasing molecule 3 (MORM3) in lipopolysaccharide (LPS) induced neonatal ALI and the possibly associated molecular mechanisms. Material/Methods For this study, 3- to 8-day old Newborn Sprague-Dawley rats were subjected to intraperitoneal injection of 3 mg/kg LPS to induce ALI. Then animals received intraperitoneal injection of carbon monoxide-releasing molecules 3 (CORM3) (8 mg/kg) or inactive CORM3 (iCORM3) for 7 consecutive days. Lung tissues were collected for histological examination and total cell counts and protein content in bronchoalveolar lavage fluid (BALF) were measured. Expression of Cx43 and necroptosis-related markers were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Results LPS exposure induced significant lung injury indicated by histological damage, increased lung wet/dry weight ratio (W/D) and increased total cell counts and protein concentration in BALF. These changes were significantly ameliorated by administration of CORM3 but not iCORM3. LPS also increased necroptosis-related markers RIP1, RIP3, and MLKL and their elevation was blocked by CORM3. CORM3 administration ameliorated LPS induced elevation of Cx43 expression and adenoviral overexpression of Cx43 abolished lung protective effect of CORM3. CORM3 administration attenuated LPS induced activation of extracellular-signal-regulated kinase (ERK) and its protection against necroptosis was abolished by ERK inhibitor U0126. Conclusions CORM3 attenuates LPS-Induced ALI in neonatal rats and its lung protective effect might be through downregulation of Cx43 to attenuate ERK signaling and ameliorate necroptosis, suggesting CORM3 as a potential therapeutic drug for ALI in neonates.

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RIP3 dependent NLRP3 inflammasome activation is implicated in acute lung injury in mice

Cited by 86 publications

References 20 publications

RIPK3 facilitates host and pathogen interactions after oralToxoplasma gondiiinfection

RIPK3 facilitates host and pathogen interactions after oralToxoplasma gondiiinfection

Necroptosis: a crucial pathogenic mediator of human disease

Carbon Monoxide Attenuates Lipopolysaccharides (LPS)-Induced Acute Lung Injury in Neonatal Rats via Downregulation of Cx43 to Reduce Necroptosis

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