Inflammatory-Dependent Bidirectional Effect of Bile Acids on NLRP3 Inflammasome and Its Role in Ameliorating CPT-11-Induced Colitis

Abstract

Irinotecan (CPT-11) in combination with 5-fluorouracil and leucovorin is a first-line chemotherapy regimen for the treatment of colorectal cancer; however, its clinical application is limited by the dose-limiting gastrointestinal toxicity of colitis. In our previous studies, several bile acids (BAs) were found significantly elevated in the colon of the CPT-11-induced rat colitis model. On the other hand, NLRP3 inflammasome has been reported to play important roles in mediating colitis. Interestingly, BA was stated to activate the NLRP3 inflammasome in some studies, while in some other reports, it showed an inhibitory effect. We assumed that the inflammatory status in different circumstances might have contributed to the controversial findings. In this study, we first discovered, under non-inflammatory conditions, that supplementing BA could activate the NLRP3 inflammasome in THP-1-differentiated macrophages and promote inflammation. In lipopolysaccharide (LPS)-induced inflammatory macrophages, however, BA inhibited the NLRP3 inflammasome and reduced inflammation. Further experiments demonstrated that Takeda G protein-coupled receptor 5 (TGR5) is essential in mediating the inhibitory effect of BA, while phospho-SP1 (p-SP1) is key to the activation. Furthermore, we applied the above findings to ameliorate CPT-11-caused colitis in rats by inhibiting SP1 with mithramycin A (MitA) or activating TGR5 using oleanolic acid (OA). Our findings may shed light on the discovery of effective interventions for reducing dose-limiting chemotherapy-induced colitis.

The relationship between atrial fibrillation and NLRP3 inflammasome: a gut microbiota perspective

“…Under non-inflammatory conditions, supplementation with BAs activated the NLRP3 inflammasome in THP-1 differentiated macrophages and promoted inflammation. However, in LPS-induced inflammatory macrophages, BAs inhibited NLRP3 inflammasomes and attenuated inflammation (83).…”

Effect of gut flora mediated‐bile acid metabolism on intestinal immune microenvironment

“…Studies have shown that TGR5 inhibits nucleotide oligomerization domain (NOD)‐like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation and caspase‐1 cleavage [79]. After inducing THP‐1 into macrophages, LPS pre‐conditioned macrophages were defined as inflammatory conditions, and those not treated with LPS were considered non‐inflammatory conditions [80]. The study of Liao et al showed that BAs inhibit NLRP3 inflammasome by TGR5 under inflammatory conditions.…”

“…The study of Liao et al showed that BAs inhibit NLRP3 inflammasome by TGR5 under inflammatory conditions. In non‐inflammatory conditions, BAs activate the NLRP3 inflammasome by regulating sp1 protein phosphorylation [80]. BAs regulate macrophages differently in inflammatory and non‐inflammatory conditions.…”

Metabolite‐derived damage‐associated molecular patterns in immunological diseases

“…However, under lipopolysaccharides (LPS)‐induced inflammatory conditions, they inhibit the NLRP3 inflammasome through Takeda G‐protein‐coupled receptor 5 (Fig. 2) [66,67]. The borderline between pro‐inflammatory and anti‐inflammatory states is ambiguous; thus, at what point BAs transform their role is an important question that needs to be further addressed.…”