Low dose of carbon monoxide (CO) has anti-inflammatory role through various signaling pathways. Cellular metabolism has been implicated in the activation of inflammation in immune cells.
Here we show that CO-dependent metabolic pathway regulates the activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome. CO-releasing molecule-3 (CORM-3) resulted in reduced glycolysis-dependent NLRP3 inflammasome activation in macrophages. The reduced mTORC1 activation by CORM-3 resulted in less glycolysis during NLRP3 inflammasome activation. CORM-3 suppressed caspase-1 activation and the secretion of IL-1β and IL-18 in macrophages in response to LPS and ATP. Moreover, CORM-3 inhibits the oligomerization of the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which is required for NLRP3-dependent caspase-1 activation. Furthermore, CORM-3-treated mice showed substantial reduction in IL-1β production by hyperglycemia in a mouse model of STZ-induced diabetes.
Our results suggest that CO regulates glycolysis-dependent NLRP3 inflammasome activation and may provide a therapeutic approach for inflammation in metabolic diseases.
D. Kim: None. S. Chun: Research Support; Self; Handok Inc.. Other Relationship; Self; Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Eli Lilly and Company. Y. Kim: None. S. Kim: None. J. Moon: None.