| Hydrogen sulfide (H2S) is a gasotransmitter produced endogenously by enzymes CSE, CBS and 3-MST, or exogenously by H2S-donor compounds. H2S modulates the inflammatory response though no clear consensus exists regarding its pro- or anti-inflammatory effects. In this study, exogenous H2S from NaHS and a novel slow H2S-releaser, FW1256, reduced inflammatory mediators secreted from LPS-stimulated mouse macrophages. FW1256 inhibited NFkappaB activation in these cells and reduced pro-inflammatory cytokine release in the LPS model of sepsis in the mouse. Using CRISPR-mediated gene editing, absence of CSE decreased iNOS and COX-2 expression in LPS-stimulated RAW264.7 cells, suggesting a differential role between exogenous and endogenous H2S. H2S from both NaHS and FW1256 also inhibited NLRP3 inflammasome activation in primary mouse macrophages by disrupting protein-protein binding in the NLRP3 inflammasome complex, preserving mitochondrial integrity and reducing mitochondrial ROS production in these cells. Altogether, exogenous H2S exerts anti-inflammatory effects in mouse macrophages via multiple molecular mechanisms. |
