Physiological concentrations of bilirubin control inflammatory response by inhibiting NF-κB and inflammasome...

Bilirubin, as the final product of heme metabolism, has both toxic and beneficial effects on humans depending on its serum concentration. So far, whether and how physiological concentrations of bilirubin influence inflammation is largely unknown. In the current study, we established inflammatory cell models of murine peritoneal macrophages (PMs) and bone marrow-derived macrophages (BMDMs) by stimulating the cells with either lipopolysaccharide (LPS) alone or with various inflammasome stimuli. In addition, a model of mouse sepsis induced by intraperitoneal injection of LPS was also employed. We found that bilirubin, although used at physiological concentrations, could control inflammation both in vitro and in vivo. In vitro, bilirubin inhibited caspase-1 maturation and IL-1β secretion in NLRP3, AIM2, and NLRC4 inflammasomes. Besides, bilirubin inhibited the secretion of TNF-α and IL-6 in LPS-primed macrophages by reduced phosphorylation of IκB-α and p65, indicating the inhibition of the NF-κB pathway. In vivo, bilirubin significantly inhibited the release of IL-1β and TNF-α, resulting in an increased survival rate of mice with LPS-induced sepsis. Our study demonstrates a protective role of physiological concentrations of bilirubin against inflammation, the mechanisms of which involve the inhibition of the NF-κB signaling pathway as well as control of the activation of inflammasomes. Bilirubin could therefore be considered an endogenous regulatory molecule modulating inflammation. In defined doses, bilirubin could be applied as a potential medication against inflammation and inflammasome-related diseases.