Editorial: Insights in cardiovascular therapeutics: 2021 – cell death, cardiovascular injuries, and novel targets of cardiovascular therapeutics

Xu, Keman; Khan, Mohsin; Snyder, Nathaniel W.; Wu, Sheng; Vázquez-Padrón, Roberto I.; Wang, Hong; Yang, Xiaofeng

doi:10.3389/fcvm.2022.981544

Cited by 1 publication

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“…Inflammasomes and inflammatory caspases, such as caspase-1 and caspase-4 (humans)/caspase-11 (mice), have two coupled functions: 1) serve as sensors for danger associated molecular patterns (DAMPs) and viral and bacterial infections-related pathogen associated molecular patterns (PAMPs) and 2) initiate inflammation signaling and promote inflammatory cell death (pyroptosis) (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), which specifically antagonize infection but can cause detrimental inflammation as well (71). Recent studies have shown promise in treating NAFLD with therapeutics targeting the nucleotide-binding domain (NOD)-, leucine-rich repeat (LRR)and pyrin domain-containing protein 3 (NLRP3) inflammasome, suggesting that targeting pyroptosis is a viable option for treating the disease (72,73).…”

Section: Introductionmentioning

confidence: 99%

Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages

et al. 2023

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IntroductionNon-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% of the population and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) and monocyte-derived macrophages, act as key players in the progression of NAFLD. Caspases are a family of endoproteases that provide critical connections to cell regulatory networks that sense disease risk factors, control inflammation, and mediate inflammatory cell death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) to induce pyroptosis and specifically defends against bacterial pathogens that invade the cytosol. However, it’s still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 and promote NAFLD.MethodsTo examine this hypothesis, we performed liver pathological analysis, RNA-seq, FACS, Western blots, Seahorse mitochondrial stress analyses of macrophages and bone marrow transplantation on HFD-induced NAFLD in WT and Casp11–/– mice.Results and DiscussionOur results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics—glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.

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Section: Introductionmentioning

confidence: 99%

Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages

et al. 2023

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Editorial: Insights in cardiovascular therapeutics: 2021 – cell death, cardiovascular injuries, and novel targets of cardiovascular therapeutics

Abstract: and Yang X ( ) Editorial: Insights in cardiovascular therapeutics:cell death, cardiovascular injuries, and novel targets of cardiovascular therapeutics.

Cited by 1 publication

References 46 publications

Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages

Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages

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