AUTHOR=Song Liqiong , Xiao Yuchun , Li Xianping , Huang Yuanming , Meng Guangxun , Ren Zhihong 

TITLE=Activation of the Nlrp3 Inflammasome Contributes to Shiga Toxin-Induced Hemolytic Uremic Syndrome in a Mouse Model

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.619096

DOI=10.3389/fimmu.2020.619096

ISSN=1664-3224

ABSTRACT=<sec><title>Objective</title><p>To explore the role of the Nlrp3 inflammasome activation in the development of hemolytic uremic syndrome (HUS) induced by Stx2 and evaluate the efficacy of small molecule Nlrp3 inhibitors in preventing the HUS.</p></sec><sec><title>Methods</title><p>Peritoneal macrophages (PMs) isolated from wild-type (WT) C57BL/6J mice and gene knockout mice (<italic>Nlrc4</italic><sup>-/-</sup>, <italic>Aim2</italic><sup>-/-</sup>, and <italic>Nlrp3</italic><sup>-/-</sup>) were treated with Stx2 <italic>in vitro</italic> and their IL-1β releases were measured. WT mice and <italic>Nlrp3</italic><sup>-/-</sup> mice were also treated with Stx2 <italic>in vivo</italic> by injection, and the biochemical indices (serum IL-1β, creatinine [CRE] and blood urea nitrogen [BUN]), renal injury, and animal survival were compared. To evaluate the effect of the Nlrp3 inhibitors in preventing HUS, WT mice were pretreated with different Nlrp3 inhibitors (MCC950, CY-09, Oridonin) before Stx2 treatment, and their biochemical indices and survival were compared with the WT mice without inhibitor pretreatment.</p></sec><sec><title>Results</title><p>When PMs were stimulated by Stx2 <italic>in vitro</italic>, IL-1β release in <italic>Nlrp3</italic><sup>-/-</sup> PMs was significantly lower compared to the other PMs. The <italic>Nlrp3</italic><sup>-/-</sup> mice treated by Stx2 <italic>in vivo</italic>, showed lower levels of the biochemical indices, alleviated renal injuries, and increased survival rate. When the WT mice were pretreated with the Nlrp3 inhibitors, both the biochemical indices and survival were significantly improved compared to those without inhibitor pretreatment, with Oridonin being most potent.</p></sec><sec><title>Conclusion</title><p>Nlrp3 inflammasome activation plays a vital role in the HUS development when mice are challenged by Stx2, and Oridonin is effective in preventing HUS.</p></sec>