Maresin1 is a potent lipid mediator exhibiting potential anti‐inflammatory activity in a variety of inflammatory diseases, however, the underlying mechanisms remain poorly understood. Excessive activation of NLRP3 inflammasome has been established in multiple inflammatory diseases. Here, we show that Maresin1 dose‐dependently inhibited the NLRP3 inflammasome activation and subsequent caspase‐1 activation and IL‐1β secretion. This inhibitory effect could be reversed by KH7 and H89, the inhibitors of the cAMP‐PKA signaling pathway. Activation of PKA kinase induced by Maresin1 led to the K63‐linked ubiquitination of NLRP3 in macrophages. Maresin1 attenuated serum IL‐1β secretion through inhibition of NLRP3 inflammasome in vivo using Nlrp3‐deficient mouse models of lipopolysaccharide (LPS)‐induced sepsis. Maresin1 also repressed MSU‐induced peritonitis. This study suggests that Maresin1 is an inhibitor of NLRP3 inflammasome activation and can be used clinically in the treatment of NLRP3 inflammasome‐driven inflammatory diseases.

BACKGROUND:Vibrio vulnifi cus inside the body could activate the NF-κB signaling pathway and initiate the inflammatory cascade. The lung is one of the earliest organs affected by sepsis associated with acute lung injury. High mobility group protein B1 (HMGB1) is an important late-acting pro-infl ammatory cytokine involving in the pathophysiology of sepsis. It is also involved in the injury process in the lung, liver and intestine. There has been no report on the involvement of HMGB1 in Vibrio vulnifi cus sepsis-induced lung injury.METHODS: Sixty rats were randomly divided into a normal control group (group A, n=10) and a Vibrio vulnificus sepsis group (group B, n=50). Sepsis was induced in the rats by subcutaneous injection of Vibrio vulnificus (concentration 6×10 8 cfu/mL, volume 0.1 mL/100g)) into the left lower limbs. The rats in group B were sacrifi ced separately 1, 6, 12, 24, and 48 hours after the infection. Their lungs were stored as specimens, lung water content was measured, and lung pathology was observed under a light microscope. The expressions of the HMGB1 gene and protein in the lungs were detected by RT-PCR and Western blot. Data were analyzed with one-way analysis of variance (ANOVA) and the LSD method for pair-wise comparison between the two groups. P<0.05 was considered statistically signifi cant.

No abstract

No abstract