Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome

• Published in: Nature communications Vol. 12; no. 1; pp. 2915 - 17
• Main Authors: Wang, Li-Qiu, Liu, Tao, Yang, Shuai, Sun, Lin, Zhao, Zhi-Yao, Li, Li-Yue, She, Yuan-Chu, Zheng, Yan-Yan, Ye, Xiao-Yan, Bao, Qing, Dong, Guang-Hui, Li, Chun-Wei, Cui, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/2; 13/21; 13/31; 13/89; 38/22; 49/90; 631/250/1933; 631/250/256/2177; 64/60; 692/420/256/2177; 692/499; 96/34; Alkanesulfonic Acids - poisoning; Animals; Apoptosis - drug effects; Apoptosis - genetics; Asthma; Asthma - chemically induced; Asthma - genetics; Asthma - metabolism; Calcium; Calcium ions; Caspase 1 - metabolism; Damage; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Environmental Pollutants - poisoning; Female; Fluorocarbons - poisoning; Gene Expression - drug effects; Humanities and Social Sciences; IL-1β; Immune system; Immunity, Innate - drug effects; Immunity, Innate - genetics; Immunity, Innate - immunology; Inflammasomes; Inflammasomes - drug effects; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation; Inflammation - chemically induced; Inflammation - genetics; Inflammation - metabolism; Innate immunity; Kidneys; Macrophages - drug effects; Macrophages - metabolism; Manufacturing industry; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial DNA; multidisciplinary; NF-κB protein; Organs; Pattern recognition; Pattern recognition receptors; Perfluoro compounds; Perfluoroalkyl & polyfluoroalkyl substances; Perfluorooctane sulfonic acid; Pollutants; Pyroptosis; Receptors; Science; Science (multidisciplinary); Substrates; Sulfonates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23201-0

Perfluoroalkyl substances (PFAS) are widely used in various manufacturing processes. Accumulation of these chemicals has adverse effects on human health, including inflammation in multiple organs, yet how PFAS are sensed by host cells, and how tissue inflammation eventually incurs, is still unclear. Here, we show that the double-stranded DNA receptor AIM2 is able to recognize perfluorooctane sulfonate (PFOS), a common form of PFAS, to trigger IL-1β secretion and pyroptosis. Mechanistically, PFOS activates the AIM2 inflammasome in a process involving mitochondrial DNA release through the Ca 2+ -PKC-NF-κB/JNK-BAX/BAK axis. Accordingly, Aim2 −/ − mice have reduced PFOS-induced inflammation, as well as tissue damage in the lungs, livers, and kidneys in both their basic condition and in an asthmatic exacerbation model. Our results thus suggest a function of AIM2 in PFOS-mediated tissue inflammation, and identify AIM2 as a major pattern recognition receptor in response to the environmental organic pollutants. The double-stranded DNA receptor AIM2 is able to sense the environmental pollutant perfluorooctane sulfonate, a prototypical perfluoro-alkyl substrate. Activation of the AIM2 pathway leads to inflammation and tissue damage via IL-1β secretion and pyroptosis of affected innate immune cells.