Targeting the TXNIP‐NLRP3 interaction with PSSM1443 to suppress inflammation in sepsis‐induced myocardial dysfunction. Issue 6 (16th January 2021) - Wang, Linhua
Abstract: Sepsis‐induced myocardial dysfunction (SIMD), a deadly symptom in sepsis patients, is mainly caused by cardiovascular inflammation. However, it remains unclear how systemic inflammation triggers and aggravates cardiovascular inflammation in the pathogenesis of SIMD. This study found that proinflammatory cytokines and H2 O2 concentrations were significantly induced in SIMD‐mice. In particular, a microarray analysis of CD63 + exosomes isolated from sham‐ and SIMD‐monocytes revealed a significant induction of thioredoxin‐interacting protein ( TXNIP ) and NLR family pyrin domain‐containing 3 ( NLRP3 ). We proved that oxidative stress caused the disassociation of the TXNIP‐TRX2 (thioredoxin 2) complex and the assembly of the TXNIP‐NLRP3 complex. In addition, this finding showed that the latter complex could be embedded into CD63 + exosomes and traffic from monocytes to the resident heart macrophages, where it activated caspase‐1 and cleaved inactive interleukin 1β (IL‐1β) and IL‐18. Furthermore, using an amplified luminescent proximity homogeneous assay (Alpha) with GST‐TXNIP and His‐NLRP3, we obtained a small molecule named PSSM1443 that could disrupt the TXNIP‐NLRP3 interaction in vitro, impairing NLRP3 downstream events. Of note, after administering PSSM1443 to the SIMD‐mice, we found the small molecule could significantly suppress the activation of caspase‐1 and the cleavage of pro‐IL‐1β and pro‐IL‐18, reducing inflammation in the SIMD‐mice. Collectively, our results reveal that monocyte‐derived exosomes harbor the overexpressed TXNIP‐NLRP3 complex, which traffics from circulating monocytes to local macrophages and promotes the cleavage of inactive IL‐1β and IL‐18 in the macrophages, aggravating cardiovascular inflammation. PSSM1443 functions as an inhibitor of the TXNIP‐NLRP3 complex and its administration can decrease inflammation in SIMD‐mice. Abstract : This study revealed that oxidative stress induces the expression of TXNIP and NLRP3 in monocytes, causing the disassociation of TXNIP‐TRX2 but the assembly of the TXNIP‐NLRP3 complex. The TXNIP‐NLRP3 complex can be embedded into exosomes and transported from monocytes to the resident macrophages localized in the heart, where this complex triggers the activation of caspase‐1 and the cleavage of pro‐IL‐1β and pro‐IL‐18. Targeting the TXNIP‐NLRP3 interaction with PSSM1443 can impair the activation of caspase‐1 and block the cleavage of pro‐IL‐1β and pro‐IL‐18.