Interruption of Helicobacter pylori-Induced NLRP3 Inflammasome Activation by Chalcone Derivatives

Abstract

Helicobacter pylori causes chronic gastritis through cag pathogenicity island (cagPAI), vacuolating cytotoxin A (VacA), lipopolysaccharides (LPS), and flagellin as pathogen-related molecular patterns (PAMPs), which, in combination with the pattern recognition receptors (PRRs) of host cells promotes the expression and secretion of inflammation-causing cytokines and activates innate immune responses such as inflammasomes. To identify useful compounds against H. pylori-associated gastric disorders, the effect of chalcone derivatives to activate the nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome was examined in an H. pylori-infected human monocytic THP-1 cell line in this study. Among the five synthetic structurally-related chalcone derivatives examined, 2'-hydroxy-4',6'-dimethoxychalcone (8) and 2'-hydroxy-3,4,5trimethoxychalcone (12) strongly blocked the NLRP3 inflammasome in H. pylori-infected THP-1 cells. At 10 µM, these compounds inhibited the production of active IL-1β, IL-18, and caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization, but did not affect the expression levels of NLRP3, ASC, and pro-caspase-1. The interruption of NLRP3 inflammasome activation by these compounds was found to be mediated via the inhibition of the interleukin-1 receptor-associated kinase 4 (IRAK4)/IκBα/NF-κB signaling pathway. These compounds also inhibited caspase-4 production associated with non-canonical NLRP3 inflammasome activation. These results show for the first time that certain chalcones could interrupt the activation of the NLRP3 inflammasome in H. pylori-infected THP-1 cells. Therefore, these chalcones may be helpful in alleviating H. pylori-related inflammatory disorders including chronic gastritis.

The Long Search for Pharmacologically Useful Anti-Inflammatory Flavonoids and Their Action Mechanisms: Past, Present, and Future

“…And these flavonoids also inhibited IκBζ activation. The inhibitory mechanisms were similar to those of flavonoids on the H. pylori -induced inflammasome pathway ( Choi et al ., 2021 ). The strongest inhibitors were apigenin and kaempferol.…”

“…In a continuing study, THP-1 cells activated with H. pylori were treated with chalcone derivatives. In H. pylori -stimulated cells, chalcones such as 2’-hydroxy-4’,6’-dimethoxyflavone and 2’-hydroxy-3,4,5-trimethoxyflavone strongly inhibited NLRP3 inflammasome activation without affecting the expression levels of the inflammasome components, NLRP3, ASC, and procaspase-1 ( Choi et al ., 2021 ). The cellular action mechanisms of the chalcones include inhibiting the interferon-1 receptor-associated kinase 4 (IRAK4) and IκBα/NF-κB signaling pathways.…”

Body mass index is associated with Helicobacter pylori infection and increased oxidative DNA damage in an obese population

“… 35 , 39 Reduced leptin levels induce appetite, which leads to overfeeding, resulting in overweight and obesity. 40 …”

Innate Immune Responses in Pediatric Patients with Gastritis—A Trademark of Infection or Chronic Inflammation?

“…Children 2022, 9, 121 2 of 17 lymphomas [1,2]. It was previously demonstrated that H. pylori-associated inflammation is closely related to the host's innate immune system since it is capable of triggering these responses via particular pathogenicity features such as cag-pathogenicity island (cagPAI) and vacuolating cytotoxin A (VacA), or pathogen-associated molecular patterns (PAMPs), involving flagellin and lipopolysaccharides (LPS) [3,4].…”

“…According to the World Health Organization, Helicobacter pylori ( H. pylori ) is a class 1 carcinogen, infecting more than 50% of the world’s population. It is well-documented that this infection might lead to chronic gastritis, peptic ulcers, gastric cancer, and mucosa-associated lymphoid tissue lymphomas [ 1 , 2 ]. It was previously demonstrated that H. pylori -associated inflammation is closely related to the host’s innate immune system since it is capable of triggering these responses via particular pathogenicity features such as cag-pathogenicity island (cagPAI) and vacuolating cytotoxin A (VacA), or pathogen-associated molecular patterns (PAMPs), involving flagellin and lipopolysaccharides (LPS) [ 3 , 4 ].…”