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.