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

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 gamma-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. ah gamma- mice had reduced macrophage and T cell activation in H. pylori-infected tissues, an altered meta bolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori-induced gastritis. Cth(-/-) is downstream of the proposed anti-inflammatory molecule, 5-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-kappa B 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.

Automated summary

Macrophages play a crucial role in the inflammatory response to Helicobacter pylori infection. Induction of cystathionine gamma-lyase (CTH) in macrophages by H. pylori promotes persistent inflammation. CTH deficiency results in altered macrophage function and metabolism, leading to decreased gastric inflammation.