Receptor-specific inhibition of pro-inflammatory cytokine secretion induced by PFAS in THP1-derived macrophages: a structure-activity relationship study

Due to their unique chemical characteristics, per- and polyfluoroalkyl substances (PFAS) have become popular compounds, particularly for producing water-resistant or non-stick coatings, which has led to their widespread presence in the environment. While there is evidence of adverse effects on human health for some PFASs, the adverse effects of many PFASs remain unknown. Moreover, PFASs have been found to reduce vaccine responses, although the mechanisms involved are not yet fully understood. The present study aims to reduce the knowledge gap on the impact of PFASs on the immune system by assessing their effect on the secretion of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α), NF-κB phosphorylation, and the activation of TLR4, TLR9, and TNFR1 in THP-1-derived macrophages. Furthermore, the study aims to establish a structure-activity relationship by examining a series of PFASs with three different headgroups and carbon chains ranging from 4 to 8 carbons. Firstly, no significant secretion of IL-6, IL-8, or TNF-α by THP-1-derived macrophages was observed after 24 h of PFASs exposure. The effect of PFASs on the release of pro-inflammatory cytokines was assessed using either LPS, TNF-α, or ODN2006, which are ligands for TLR4, TNFR1, and TLR9, respectively. Pre-exposure to PFASs decreased the secretion of IL-1β, IL-6, IL-8, and TNF-α in response to LPS stimulation. Similarly, IL-8 secretion after stimulation by TNF-α was reduced by pre-exposure to PFASs. However, PFASs had no effect on IL-8 secretion after stimulation by ODN2006. PFOA, PFOS, and 6:2 FTOH reduced NF-κB phosphorylation after LPS stimulation. A structure-activity relationship was derived for the inhibition of PFASs on cytokine secretion. PFASs with a fluorotelomer headgroup showed the strongest potential to inhibit cytokine release, followed by PFASs with sulfonic and carboxylic headgroups, respectively. A consistent effect of carbon-chain length was observed for each tested PFAS with different headgroups: the inhibitory potential of PFASs increases with the number of carbons.