Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages.

Inflammasomes are cytosolic protein complexes that promote the cleavage of caspase-1, which leads to the maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. Among the known inflammasomes, the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3)-dependent inflammasome is critically involved in the pathogenesis of various acute or chronic inflammatory diseases. Carbon monoxide (CO), a gaseous molecule physiologically produced in cells and tissues during heme catabolism, can act as an anti-inflammatory molecule and a potent negative regulator of Toll-like receptor signaling pathways. To date, the role of CO in inflammasome-mediated immune responses has not been fully investigated. Here, we demonstrated that CO inhibited caspase-1 activation and the secretion of IL-1β and IL-18 in response to lipopolysaccharide (LPS) and ATP treatment in bone marrow-derived macrophages. CO also inhibited IL-18 secretion in response to LPS and nigericin treatment, another NLRP3 inflammasome activation model. In contrast, CO did not suppress IL-18 secretion in response to LPS and poly(dA:dT), an absent in melanoma 2 (AIM2)-mediated inflammasome model. LPS and ATP stimulation induced the formation of complexes between NLRP3 and apoptosis-associated speck-like protein, or NLRP3 and caspase-1. CO treatment inhibited these molecular interactions that were induced by LPS and ATP. Furthermore, CO inhibited mitochondrial ROS generation and the decrease of mitochondrial membrane potential induced by LPS and ATP in macrophages. We also observed that the inhibitory effect of CO on the translocation of mitochondrial DNA into the cytosol was associated with suppression of cytokine secretion. Our results suggest that CO negatively regulates NLRP3 inflammasome activation by preventing mitochondrial dysfunction.

Jung SS ，Moon JS ，Xu JF ，Ifedigbo E ，Ryter SW ，Choi AM ，Nakahira K ... -  《-》

Aloe vera downregulates LPS-induced inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages.

Budai MM ，Varga A ，Milesz S ，Tőzsér J ，Benkő S ... -  《-》

Non-transcriptional regulation of NLRP3 inflammasome signaling by IL-4.

Hwang I ，Yang J ，Hong S ，Ju Lee E ，Lee SH ，Fernandes-Alnemri T ，Alnemri ES ，Yu JW ... -  《-》

Comparison of Inhibitory Capacities of 6-, 8- and 10-Gingerols/Shogaols on the Canonical NLRP3 Inflammasome-Mediated IL-1β Secretion.

Ho SC ，Chang YH 《MOLECULES》

Lipopolysaccharide/adenosine triphosphate induces IL‑1β and IL-18 secretion through the NLRP3 inflammasome in RAW264.7 murine macrophage cells.

Xie Q ，Shen WW ，Zhong J ，Huang C ，Zhang L ，Li J ... -  《-》