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Carbon monoxide regulates glycolysis-dependent NLRP3 inflammasome activation in macrophages.

Biochemical and biophysical research communications (2017-09-25)
Do Won Lee, Ha Young Shin, Ji Hun Jeong, Jaeseok Han, Seongho Ryu, Kiichi Nakahira, Jong-Seok Moon
RESUMO

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. However, the mechanisms by which CO-dependent metabolic regulation affect the immune response remain unclear. 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 interleukin (IL)-1β and IL-18 in macrophages in response to lipopolysaccharide (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 streptozotocin (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.

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Sigma-Aldrich
Lipopolissacarídeos, purified by trichloroacetic acid extraction
Sigma-Aldrich
Poly(deoxyadenylic-thymidylic) acid sodium salt, double-stranded alternating copolymer
Sigma-Aldrich
CORM-3