Corticosterone Inhibits LPS-Induced NLRP3 Inflammasome Priming in Macrophages by Suppressing Xanthine Oxidase

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.

Benzyl Isothiocyanate Attenuates Inflammasome Activation in Pseudomonas aeruginosa LPS-Stimulated THP-1 Cells and Exerts Regulation through the MAPKs/NF-κB Pathway

“…This result suggests that BITC inhibits the IL-1β production by suppressing the P. aeruginosa LPS-induced signaling pathways. Several studies have reported that LPS stimulates IL-1β production through the activation of inflammasomes [30,31]. In this regard, we investigated whether BITC inhibits the activation of inflammasomes such as NLRP3 and caspase-1 in the cytosol.…”

Polarized Cytokine Release Triggered by P2X7 Receptor from Retinal Pigmented Epithelial Cells Dependent on Calcium Influx

“…Whether the P2X7 receptor can also trigger cytokine upregulation and release independent of IL-1β is less well studied. This is relevant as the NLRP3 inflammasome requires "priming" to increase expression of key components, such as NLRP3 itself, before the activation stage can occur [6], and priming of inflammasome components may be rate-limiting in chronic age-dependent diseases [7]. The involvement of the P2X7 receptor in release of cytokines other than IL-1β may thus have implications for earlier stages in chronic inflammatory diseases.…”

NLRP3 Inflammasome-Targeting Nanomicelles for Preventing Ischemia–Reperfusion-Induced Inflammatory Injury

“…In all the above behavioral studies, we used LPS as a correlate to induce NLRP3-mediated inflammasome, , and the results obtained were similar to those of the MCAO treated groups. The recovery of behavioral function in Sham and MCAO rats was shown to be comparable across the functional outcomes.…”