Human parvovirus B19 nonstructural protein NS1 activates NLRP3 inflammasome signaling in adult­onset Still's disease.

ABSTRACT

Dysregulation of inflammasomes serves a pathogenic role in autoinflammatory diseases (AIDs) and adult-onset Still's disease (AOSD) has been categorized as an AID. The present study investigated the expression of NLR family pyrin domain containing proteins (NLRPs) inflammasome in patients with AOSD, the effect of inflammasome inhibitors on NLRP3 signaling and whether human parvovirus B19­associated antigens can activate NLRP3 in patients with AOSD. mRNA expression levels of NLRPs in peripheral blood mononuclear cells (PBMCs) from 34 patients with AOSD and 14 healthy individuals were determined using reverse transcription­quantitative polymerase chain reaction. Protein expression of NLRP3 was evaluated by western blotting. Supernatant cytokine levels were measured by ELISA. Among the NLRPs investigated in the present study, NLRP3 transcripts were markedly elevated and expression of NLRP2, NLRP7 and NLRP12 was decreased in patients with AOSD compared with the controls. Treatment with NLRP3 inhibitors significantly reduced downstream NLRP3 signaling in PBMCs form patients with AOSD. B19­nonstructural protein (NS)1 stimulation of PBMCs from patients with AOSD induced significant upregulation of transcript levels of NLRP3, caspase­1 and interleukin (IL)­1ß compared with PBMCs from healthy controls. B19­NS1 stimulation of PBMCs from patients with AOSD induced significant increase in supernatant levels of IL­1ß and protein expression of NLRP3, caspase­1, IL­1ß, and IL­18 compared with healthy controls. Elevated expression of NLRP3 and its downstream inflammasome signaling components in patients with AOSD indicated a potential pathogenic role of B19­NS1. Thus, B19­NS1 may induce expression of IL­1ß and IL­18 through activation of caspase­1­associated NLRP3­inflammasome in AOSD.