Low-dose PFNA exposure exacerbates intestinal inflammation via caspase-11-dependent noncanonical NLRP3 inflammasome activation in macrophages.

INTRODUCTION Per- and polyfluoroalkyl substances (PFASs) have been implicated in promoting the progression of intestinal inflammation. However, the specific mechanisms remain unclear.

Objectives

This study aimed to elucidate how PFASs exacerbate inflammatory bowel disease (IBD) progression by directly influencing macrophages, investigate the underlying molecular mechanisms, and explore potential interventions.

Methods

Primary mouse peritoneal macrophages (PMs) and a chronic colitis model were utilized to investigate the impacts of three typical PFASs, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), on the progression of IBD to clarify the underlying mechanisms and potential interventions.

Results

Our study found that PFNA induced significant proinflammatory responses, characterized by marked upregulation of IL-1β and IL-18 under environmentally relevant concentrations. Mechanistically, PFNA activated the caspase-11-dependent noncanonical NLRP3 inflammasome, thereby inducing dose-dependent upregulation of caspase-1, N-GSDMD, IL-1β, and IL-18. Both caspase-11 knockdown and Z-VAD-FMK inhibition attenuated these inflammatory effects. Molecular docking suggested that PFNA might induce NLRP3 inflammasome activation by interacting with pro-caspase-11. In vivo, PFNA also aggravated IBD progression through the same pathway. Conversely, based on our previous study, myricetin was found to alleviate PFNA-induced inflammation by inhibiting the caspase-11/NLRP3 axis.

Conclusion

Our study reveals a molecular axis through which PFNA exacerbates intestinal inflammation and identifies myricetin as a potential intervention for IBD associated with PFNA exposure. These findings provide insights into the mechanisms of PFNA-induced intestinal toxicity and may guide the development of strategies to mitigate PFNA-associated intestinal inflammation.