Cystathionine γ-lyase exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation

Latour, Yvonne L.; Sierra, Johanna C.; Finley, Jordan L.; Asim, Mohammad; Barry, Daniel P.; Allaman, Margaret M.; Smith, Thaddeus M.; McNamara, Kara M.; Luis, Paula B.; Schneider, Claus; Jacobse, Justin; Goettel, Jeremy A.; Calcutt, M. Wade; Rose, Kristie L.; Schey, Kevin L.; Milne, Ginger L.; Delgado, Alberto; Piazuelo, M. Blanca; Paul, Bindu D.; Snyder, Solomon H.; Gobert, Alain P.; Wilson, Keith T.

doi:10.1172/jci.insight.155338

Cited by 16 publications

(8 citation statements)

References 55 publications

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“…More importantly, we also found that the expression of Cth, a key enhancer of macrophage activation [ 29 ], was significantly upregulated after I/R surgery. Combined with the PCA results and heatmap analyses, these results suggest that Cth may be a key gene that drives macrophage efferocytosis after I/R.…”

Section: Resultsmentioning

confidence: 97%

Cystathionine gamma-lyase (Cth) induces efferocytosis in macrophages via ERK1/2 to modulate intestinal barrier repair

et al. 2023

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Background The inflammatory response induced by intestinal ischaemia‒reperfusion injury (I/R) is closely associated with infectious complications and mortality in critically ill patients, and the timely and effective clearance of apoptotic cells is an important part of reducing the inflammatory response. Studies have shown that the efferocytosis by phagocytes plays an important role. Recently, studies using small intestine organoid models showed that macrophage efferocytosis could promote the repair capacity of the intestinal epithelium. However, no studies have reported efferocytosis in the repair of I/R in animal models. Results We used an in vivo efferocytosis assay and discovered that macrophage efferocytosis played an indispensable role in repairing and maintaining intestinal barrier function after I/R. In addition, the specific molecular mechanism that induced macrophage efferocytosis was Cth-ERK1/2 dependent. We found that Cth drove macrophage efferocytosis in vivo and in vitro. Overexpression/silencing Cth promoted/inhibited the ERK1/2 pathway, respectively, which in turn affected efferocytosis and mediated intestinal barrier recovery. In addition, we found that the levels of Cth and macrophage efferocytosis were positively correlated with the recovery of intestinal function in clinical patients. Conclusion Cth can activate the ERK1/2 signalling pathway, induce macrophage efferocytosis, and thus promote intestinal barrier repair.

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Section: Resultsmentioning

confidence: 97%

Cystathionine gamma-lyase (Cth) induces efferocytosis in macrophages via ERK1/2 to modulate intestinal barrier repair

et al. 2023

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“…Similar observations were reported in other animal studies, likely owing to the impaired immune response for H pylori clearance. 49 , 50 …”

Section: Discussionmentioning

confidence: 99%

BRD4 Regulates Glycolysis-Dependent Nos2 Expression in Macrophages Upon H pylori Infection

Modi,

Chen,

Dong

et al. 2024

Cellular and Molecular Gastroenterology and Hepatology

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“…In addition, we also found that quercetin treatment suppressed macrophage M1 polarization and the production of iNOS and COX‐2. It has been revealed that macrophages play significant roles in the inflammatory response to HP infection in the human stomach (Latour et al, 2022). Macrophages are a diverse group of white blood cells whose primary function is phagocytosis to eliminate pathogens; monocyte‐derived macrophages are pivotal components of the innate immune response (Murray & Wynn, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…M1 macrophages are recognized to have pro‐inflammatory, antibacterial, and anticancer activities (Sica & Mantovani, 2012). During HP infection, macrophages show an M1‐like phenotype and express chemokines and inflammatory cytokines to recruit and activate other innate cells and the robust adaptive T cell response (Gan et al, 2017; Latour et al, 2022; Wilson et al, 1996). In addition, M1 macrophages lead to the secretion of the inflammatory enzymes iNOS and COX‐2, the core mediators of both HP‐related gastritis and carcinogenesis (Cho et al, 2021; Lu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Quercetin ameliorates Helicobacter pylori‐induced gastric epithelial cell injury by regulating specificity protein 1/lipocalin 2 axis in gastritis

Wang,

Zhou,

et al. 2023

J of Applied Toxicology

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Helicobacter pylori (HP) infection is the main cause of most cases of gastritis. Quercetin has been shown to have anti‐inflammatory, anti‐bacterial, and antiviral activities and has been demonstrated to be involved in HP‐induced gastric mucosa injury. Moreover, the secretory protein lipocalin‐2 (LCN2) was elevated in HP‐infected gastric mucosa. Thus, this work aimed to study the interaction between quercetin and LCN2 in HP‐triggered gastric injury during gastritis. Human gastric epithelial cell line GES‐1 cells were exposed to HP for functional experiments. Cell viability, apoptosis, and inflammation were evaluated by cell counting kit‐8, flow cytometry, and enzyme‐linked immunosorbent assay, respectively. Levels of genes and proteins were tested using quantitative reverse transcription polymerase chain reaction and western blotting analyses. The interaction between LCN2 and specificity protein 1 (SP1) was validated using chromatin immunoprecipitation assay and dual‐luciferase reporter assay. Thereafter, we found quercetin treatment suppressed HP‐induced GES‐1 cell apoptotic and inflammatory injury and macrophage M1 polarization. LCN2 was highly expressed in HP‐infected gastritis patients and HP‐infected GES‐1 cells, while quercetin reduced LCN2 expression in HP‐infected GES‐1 cells; moreover, LCN2 knockdown reversed HP‐induced GES‐1 cell injury and macrophage M1 polarization, and forced expression of LCN2 abolished the protective effects of quercetin on GES‐1 cells under HP infection. Mechanistically, SP1 bound to LCN2 promoter and promoted its transcription. Also, SP1 overexpression counteracted the functions of quercetin on HP‐stimulated GES‐1 cells. In all, quercetin ameliorated HP‐induced gastric epithelial cell apoptotic and inflammatory injuries, and macrophage M1 polarization via the SP1/LCN2 axis.

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Cystathionine γ-lyase exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation

Cited by 16 publications

References 55 publications

Cystathionine gamma-lyase (Cth) induces efferocytosis in macrophages via ERK1/2 to modulate intestinal barrier repair

Cystathionine gamma-lyase (Cth) induces efferocytosis in macrophages via ERK1/2 to modulate intestinal barrier repair

BRD4 Regulates Glycolysis-Dependent Nos2 Expression in Macrophages Upon H pylori Infection

Quercetin ameliorates Helicobacter pylori‐induced gastric epithelial cell injury by regulating specificity protein 1/lipocalin 2 axis in gastritis

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