# PPAR-gamma regulates PFAS-mediated proinflammatory cytokines in lung epithelial cells

## TL;DR

This study shows that PPAR-gamma signaling helps reduce inflammation caused by PFAS in lung cells, and activating it can counteract harmful effects.

## Contribution

The study reveals a novel role of PPARγ in mediating PFAS-induced inflammation and suggests its activation as a potential therapeutic strategy.

## Key findings

- PFAS exposure increased IL-6 and IL-8 secretion in lung epithelial cells.
- PPARγ agonists reduced PFAS-induced cytokine levels, while its antagonist increased them.
- PFOS exposure in mice reduced lung PPARγ protein levels.

## Abstract

Per and polyfluoroalkyl substances (PFAS), including the legacy compound perfluorooctanesulfonic acid (PFOS), are persistent organic pollutants with long biological half-lives. Emerging evidence suggests a significant accumulation of PFAS/PFOS in the human lung, potentially contributing to inflammation and altered immune responses. However, the role of peroxisome proliferator-activated receptor gamma (PPARγ) signaling in PFAS/PFOS-induced pulmonary toxicity remains unclear.

Primary human bronchial epithelial (NHBE) cells were exposed to 15 µM binary PFAS mixture (PFOS + PFOA) or quaternary mixture (PFOS, PFOA, PFHxS, GenX) with or without the PPARγ antagonist (15 µM) and/or the PPARγ agonists rosiglitazone (10 µM) or pioglitazone (10 µM) for 24 h. BALB/c mice were orally administered PFOS (2 mg/kg/day) or vehicle control for 2 weeks.

In NHBE cells, PFAS exposure significantly increased IL-6 and IL-8 secretion. Treatment with rosiglitazone or pioglitazone reversed these cytokine increases, whereas co-treatment with the PPARγ antagonist elevated IL-6 and IL-8 levels compared to PFAS exposure alone in epithelial cells. PFOS exposure in mice caused a reduction in lung PPARγ protein levels, while PPARα expression remained unchanged.

These findings demonstrate that PFAS-induced pro-inflammatory cytokines is mediated, at least in part, through PPARγ signaling, and that pharmacological activation of PPARγ signaling can attenuate PFAS-triggered pro-inflammatory cytokine responses in lung epithelial cells.