Licochalcone B specifically inhibits the NLRP3 inflammasome by disrupting NEK7‐NLRP3 interaction

Abstract

The activation of the nucleotide oligomerization domain (NOD)like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is related to the pathogenesis of a wide range of inflammatory diseases, but drugs targeting the NLRP3 inflammasome are still scarce. In the present study, we demonstrated that Licochalcone B (LicoB), a main component of the traditional medicinal herb licorice, is a specific inhibitor of the NLRP3 inflammasome. LicoB inhibits the activation of the NLRP3 inflammasome in macrophages but has no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, LicoB directly binds to NEK7 and inhibits the interaction between NLRP3 and NEK7, thus suppressing NLRP3 inflammasome activation. Furthermore, LicoB exhibits protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including lipopolysaccharide (LPS)-induced septic shock, MSU-induced peritonitis and nonalcoholic steatohepatitis (NASH). Our findings indicate that LicoB is a specific NLRP3 inhibitor and a promising candidate for treating NLRP3 inflammasome-related diseases.

Role of NLRP3 Inflammasome in Rheumatoid Arthritis

“…Compound 149-01, an analog of RRX001 without high-energy nitro functional groups, was recently identified as a potent and specific NLRP3 inhibitor that inhibits NLRP3 activation and attenuates inflammatory responses in vivo and vitro by preventing NLRP3 from binding to NEK7 ( 123 ). Licochalcone B (LicoB), a major component of traditional medicinal herb licorice, was also found to disturb the interaction between NLRP3 and NEK7, thus inhibiting NLRP3 activation ( 124 ). LL-Z1640-2(LLZ) is a preclinical drug that primarily targets TGF-β-activated kinase-1(TAK1), which produces a variety of proinflammatory cytokines and inflammatory mediators in RA.…”

NLRP3 Inflammasome Pharmacological Inhibitors in Glycyrrhiza for NLRP3-Driven Diseases Treatment: Extinguishing the Fire of Inflammation

“… 14 , 37 Although the content of Lico B ( Figure 2B ) in Glycyrrhiza is relatively low, it has a strong anti-NLRP3 inflammasome effect. Our previous studies have shown that Lico B could specifically suppress NLRP3 inflammasome activation via binding to NEK7 and inhibiting the interaction between NLRP3 and NEK7 in BMDMs, THP-1 cells and human peripheral blood mononuclear cells (PBMCs) 38 ( Figure 3 ). In vivo experiments show that Lico B ameliorates LPS-induced septic shock characterized by improving survival rate, inhibiting IL-1β production, reducing the number of peritoneal exudative cells and peritoneal macrophages; Meanwhile, MSU-induced peritonitis, and methionine- and choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis are significantly ameliorated by Lico B through targeting NLRP3 inflammasome.…”

“…In vivo experiments show that Lico B ameliorates LPS-induced septic shock characterized by improving survival rate, inhibiting IL-1β production, reducing the number of peritoneal exudative cells and peritoneal macrophages; Meanwhile, MSU-induced peritonitis, and methionine- and choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis are significantly ameliorated by Lico B through targeting NLRP3 inflammasome. 38 Taking these studies into consideration, we firmly believe that with further investigation of its pharmacological effects will lead to Lico B becoming a promising candidate in the treatment of NLRP3-related diseases.…”

“…14,37 Although the content of Lico B (Figure 2B) in Glycyrrhiza is relatively low, it has a strong anti-NLRP3 inflammasome effect. Our previous studies have shown that Lico B could specifically suppress NLRP3 inflammasome activation via binding to NEK7 and inhibiting the interaction between NLRP3 and NEK7 in BMDMs, THP-1 cells and human peripheral blood mononuclear cells (PBMCs) 38 (Figure 3). In vivo…”

“…Caspase-1(p10) ↓, IL-1β↓, mitochondrial reactive oxygen species production↓ [36] Intradermal infection of P. acnes mouse mode Skin inflammation↓, caspase-1 activity↓, IL-1β↓ [36] Lico B BMDMs, THP-1 cells, and human PBMCs IL-1β↓, caspase-1 activity↓, caspase-1 p20↓, bind to NEK7↑, the interaction between NLRP3 and NEK7↓ [38] LPS-induced septic shock Mouse survival↑, IL-1β↓, the number of peritoneal exudative cells↓, peritoneal macrophages↓ [38] MSU-induced mouse peritonitis IL-1β↓, the number of peritoneal exudates↓, neutrophils↓ [38] MCD diet-induced NASH mouse model Liver steatosis↓, balloon dilatation↓, fibrosis↓, the protein level of active caspase-1 in liver tissue↓, the pro-fibrotic marker alpha smooth muscle actin (α-SMA) ↓, mRNA expression of col1a1↓, TNF-α↓, IL-1β↓ and IL-18↓, serum IL-18↓ [38] Liquiritigenin Potassium oxonate-induced hyperuricemic rat model…”