Cystathionine γ-lyase exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling
Yvonne L Latour1,2, Johanna C Sierra2,3, Jordan L Finley2
1Department of Pathology, Microbiology, and Immunology.
Abstract:
Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world's population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme cystathionine γ-lyase (CTH) is upregulated in humans and mice with H. pylori infection. Here, we show that induction of CTH in macrophages by H. pylori promoted persistent inflammation. Cth-/- mice had reduced macrophage and T cell activation in H. pylori-infected tissues, an altered metabolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori-induced gastritis. CTH is downstream of the proposed antiinflammatory molecule, S-adenosylmethionine (SAM). Whereas Cth-/- mice exhibited gastric SAM accumulation, WT mice treated with SAM did not display protection against H. pylori-induced inflammation. Instead, we demonstrated that Cth-deficient macrophages exhibited alterations in the proteome, decreased NF-κB activation, diminished expression of macrophage activation markers, and impaired oxidative phosphorylation and glycolysis. Thus, through altering cellular respiration, CTH is a key enhancer of macrophage activation, contributing to a pathogenic inflammatory response that is the universal precursor for the development of H. pylori-induced gastric disease.
Insights
Helicobacter pylori infection upregulates cystathionine γ-lyase (CTH) in macrophages, promoting persistent inflammation and gastric disease. CTH deficiency reduces inflammation by altering macrophage metabolism and activation.
Area of Science:
- Immunology
- Gastroenterology
- Cellular Metabolism
Background:
- Helicobacter pylori infection affects half the global population and is a major cause of gastric cancer.
- Macrophage immunometabolism is critical for regulating immune cell activation and function.
- Cystathionine γ-lyase (CTH) is upregulated in H. pylori infection, but its role in pathogenesis is unclear.
Purpose of the Study:
- To investigate the role of cystathionine γ-lyase (CTH) in macrophage activation and inflammation during H. pylori infection.
- To elucidate the mechanisms by which CTH influences cellular respiration and immune responses.
- To determine if CTH is a potential therapeutic target for H. pylori-induced gastric disease.
Main Methods:
- Utilized Cth-/- mice and wild-type (WT) mice infected with H. pylori.
- Analyzed macrophage and T cell activation markers in infected tissues.
- Performed metabolomic and proteomic analyses of Cth-deficient macrophages.
- Assessed cellular respiration, including oxidative phosphorylation and glycolysis.
Main Results:
- H. pylori induction of CTH in macrophages promotes persistent inflammation.
- Cth-/- mice exhibited reduced immune cell activation, altered metabolomes, and decreased gastritis.
- CTH deficiency impaired macrophage NF-κB activation, reduced activation markers, and altered cellular respiration.
- S-adenosylmethionine (SAM) accumulated in Cth-/- mice, but SAM treatment did not protect WT mice.
Conclusions:
- CTH is a key enhancer of macrophage activation by altering cellular respiration.
- CTH contributes to the pathogenic inflammatory response driving H. pylori-induced gastric disease.
- Targeting CTH may offer a novel therapeutic strategy for H. pylori-associated pathologies.
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