Targeting Peroxiredoxin 1 by a Curcumin Analogue, AI-44, Inhibits NLRP3 Inflammasome Activation and Attenuates Lipopolysaccharide-Induced Sepsis in Mice

Abstract

Aberrant activation of the NLRP3 inflammasome contributes to the onset and progression of various inflammatory diseases, making it a highly desirable drug target. In this study, we screened a series of small compounds with anti-inflammatory activities and identified a novel NLRP3 inflammasome inhibitor, AI-44, a curcumin analogue that selectively inhibited signal 2 but not signal 1 of NLRP3 inflammasome activation. We demonstrated that AI-44 bound to peroxiredoxin 1 (PRDX1) and promoted the interaction of PRDX1 with pro-Caspase-1 (CASP1), which led to the suppression of association of pro-CASP1 and ASC. Consequently, the assembly of the NLRP3 inflammasome was interrupted, and the activation of CASP1 was inhibited. Knockdown of PRDX1 significantly abrogated the inhibitory effect of AI-44 on the NLRP3 inflammasome. Importantly, AI-44 alleviated LPS-induced endotoxemia in mice via suppressing NLRP3 inflammasome activation. Taken together, our work highlighted PRDX1 as a negative regulator of NLRP3 inflammasome activation and suggested AI-44 as a promising candidate compound for the treatment of sepsis or other NLRP3 inflammasome-driven diseases.

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

“…Our current results are strongly supportive of the validity of this approach by showing that genetic silencing of PRDX1 in TNBC cell lines amplifies the efficacy of one of the most promising prooxidant approaches, i.e., the combination of Asc and Men (Figure 3 and Figure S5D,E). The difficulty of PRDX1 targeting in cancer in the clinical settings is related to the fact that chemical agents known to inhibit PRDX1, such as adenanthin [34,43], AI-44 [44], or frenolicin B [45], or the PRDX1-related antioxidant enzymatic system, such as SK053 [14] or AUR [13], are in most cases fairly unselective and/or do not possess satisfactory pharmacokinetics. The exception for the latter is AUR, the clinically approved drug primarily used in rheumatology and suggested in numerous other indications [46].…”

The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury

“…Different regulators may positively modulate NLRP3 inflammasome such as DDX3X, GBP5 and cathepsin, thus inducing NLRP3 oligomerization and promoting ASC assembly [ 89 , 90 , 91 ]. On the other hand, HSP70, PRDX1, NLRC3, SHP and POPs may negatively modulate NLRP3 assembly, acting on NLRP3 itself or inhibiting the formation of NLRP3/ASC complex or the interaction between ASC and procaspase-1 [ 92 , 93 , 94 , 95 , 96 ]. Post-translational modification may also promote NLRP3 assembly and interaction, in fact, the dephosphorylation of pyrin domain mediated by PP2A significantly inhibited NLRP3 inflammasome activation thus blocking ASC assembly that requires pyrin domain (PYD)–PYD interactions [ 97 ].…”

Prdx1 Reduces Intracerebral Hemorrhage-Induced Brain Injury via Targeting Inflammation- and Apoptosis-Related mRNA Stability

“…Although Prdx1, an RBP (Baltz et al, 2012;Castello et al, 2012;Kim et al, 2012;Kwon et al, 2013;Sebestyén et al, 2016), has been shown to be elevated after ICH (Nakaso et al, 2000), its roles in brain injury after ICH are still largely unknown. Prdx1 is a member of the peroxiredoxin family (Wood et al, 2003) and has been shown to be involved in regulating many pathological processes, such as redox reactions (Yamaguchi et al, 1993), inflammatory responses, apoptosis (Liu et al, 2014(Liu et al, , 2018Min et al, 2018;Lu et al, 2019), and tumorigenesis (Hoshino et al, 2005;Cao et al, 2009). These findings suggest that Prdx1 may also play important roles in regulating the above-mentioned pathological processes to influence the brain injury caused by ICH.…”