Abstract
Following traumatic insult and associated pathogen infection, innate immunity is activated during the perioperative period, especially the NLRP3 inflammasome in macrophages. The neuroendocrine response is also rapidly activated to regulate excessive inflammation; however, the molecular mechanisms are still not completely clear. This study is aimed at investigating the modulation of NLRP3 inflammasome priming by endogenous glucocorticoids (corticosterone, CORT) and its relationship with xanthine oxidase (XO). RAW264.7 murine macrophages were stimulated with LPS (1 μg/ml). LPS-induced NLRP3 expression was pretreated by CORT at different concentrations (0-900 ng/ml). Then, the effect of higher concentrations of CORT (700 ng/ml) on LPS-induced NLRP3 expression and the effect of allopurinol (250 μg/ml) were observed. Finally, the effects of a CORT antagonist (RU486) on XO expression and activity and NLRP3 expression in macrophages were further analyzed. Supernatant levels IL-1β and IL-18 were measured. The results showed that LPS-induced NLRP3 expression was upregulated further by pretreatment with CORT (300 ng/ml) (P < 0.05); however, higher concentrations of CORT (greater than 700 ng/ml) downregulated NLRP3 expression (P < 0.01) and the expression and activity of XO (P < 0.05 and P < 0.01, respectively). Allopurinol significantly inhibited NLRP3 expression. However, XO expression and activity, NLRP3 expression, and supernatant IL-1β and IL-18 levels were significantly increased in the RU486 group compared with the CORT group. In conclusion, our results suggested that CORT inhibits LPS-induced NLRP3 inflammasome priming in macrophages. The underlying mechanism is related to the modulation of XO expression and activity, which may be involved in priming and activating the NLRP3 inflammasome.
Highlights
An initial traumatic insult disrupts macrobarriers such as the skin, as well as microbarriers such as cell membranes, and constitutes the beginning of a rapidly activated immune response
NLRP3 mRNA was increased significantly compared with that of the control (Fig. S1). These results indicate that in our model system, LPS enhances NLRP3 expression consistently, leading to NLRP3 inflammasome priming in macrophages
This study showed that endogenous glucocorticoid CORT modulated NLRP3 expression and its inflammasome priming in macrophages to regulate inflammation, and higher concentrations of CORT suppressed LPS-induced NLRP3 expression and its inflammasome activity, which was closely related to xanthine oxidase (XO)
Summary
An initial traumatic insult disrupts macrobarriers such as the skin, as well as microbarriers such as cell membranes, and constitutes the beginning of a rapidly activated immune response. The body’s mechanical barriers are destroyed, making it possible for pathogens to invade and amplify a vicious cycle of tissue injury and damaging immunological processes [1,2,3]. Inflammation is characteristic of activation of innate immunity, which attempts to clear damaged tissues and invading pathogens, with the ultimate goal of maintaining homeostasis. In contrast to transmembrane TLRs localized either to the cell surface or within endosomes [6], NLRP3 is a cytosolic sensor that mostly detects intracellular stimuli. In addition to its critical role in the detection and control of diverse intracellular pathogens [7], NLRP3 senses and reacts to damage-
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