Nat Commun|Cui Jun/Li Chunwei collaborate to reveal that organic pollutants induce activation of innate immune receptor AIM2

Responsible Editor | Perfluoroalkyl substances (PFAS) have good hydrophobicity, oleophobicity and chemical stability, and are widely used in industrial and civil fields such as detergents, water-resistant coatings and food packaging [1].

However, PFAS is difficult to be degraded in the environment, leading to its widespread presence in natural environmental media (such as water, soil and air) and animals and plants.

The human body can be exposed to PFAS through various ways such as drinking water and food, inhaling air and dust [1].

A large number of epidemiological studies have shown that PFAS accumulated in the body has adverse effects on human health and is significantly related to the risk of immune regulation (such as allergic asthma), metabolic disorders such as non-alcoholic liver disease, and neurodevelopmental delays [ 2-4].

Perfluorooctane sulfonate (PFOS) is the most typical and widely used perfluoroalkyl compound.
PFOS and its salt compounds were included in the “Stockholm Convention on Persistent Organic Pollutants” in 2009.
Control list.

Existing cytological and animal experiments have shown that PFOS can cause inflammation and tissue damage [5-6].
However, the molecular mechanism of inflammation and damage caused by PFOS remains to be clarified; because PFOS is an exogenous stimulus, Solving the mechanism of how the body's cells recognize PFOS and trigger the inflammatory response is the key to elucidating the mechanism of PFOS toxicity and tissue damage.On May 18, 2021, Professor Jun Cui’s research group from the School of Life Sciences, Sun Yat-sen University collaborated with the research group of Professor Li Chunwei from the First Affiliated Hospital of Sun Yat-Sen University, and published the title Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 in Nature Communications.
The research paper of inflammasome, for the first time, revealed the new mechanism of the organic pollutant PFOS, which induces the activation of AIM2 inflammasomes and promotes inflammation and tissue damage.

The study found that PFOS can cause the release of inflammatory factors (IL-1β, TNF-α and IL-6), cell death and tissue damage at the cellular and animal levels.

Further mechanism studies have found that PFOS can up-regulate the free Ca2+ content in the cytoplasm, activate the downstream Ca2+-dependent PKC-NF-κB/JNK signal axis, thereby promoting the transcription of inflammatory genes and the activation of JNK.

The phosphorylated JNK can promote the translocation of BAX in the cytoplasm to the mitochondrial membrane and bind with BAX or CypD on the mitochondria, and promote the release of mitochondrial DNA into the cytoplasm and bind and activate the AIM2 inflammasome, thereby inducing inflammation.
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By constructing an acute PFOS exposure model and a chronic PFOS exposure aggravated asthma model, it was found that the acute tissue (liver, lung, and kidney) damage induced by PFOS was significantly reduced in AIM2 gene-deficient mice, and PFOS aggravated ovalbumin (OVA) induced The symptoms of asthma were significantly reduced, revealing that AIM2 inflammasomes play a key role in the tissue damage and asthma exacerbation caused by PFOS.

Figure: PFOS activates the AIM2 inflammasome through the Ca2+-PKC-NF-κB/JNK-BAX/BAK-mtDNA signal axis to cause tissue inflammation.

In summary, this study reveals that PFOS induces mitochondrial non-oxidized DNA to be released into the cytoplasm through the pores formed by BAX/BAK oligomers or the pores formed by BAX/CypD, which are sensed by the AIM2 inflammasome, leading to inflammation.
The molecular mechanism (as shown in the figure above) provides an important theoretical reference for the development of treatment and intervention for PFOS-related inflammatory diseases.

It is reported that Professor Cui Jun and Professor Li Chunwei are the corresponding authors of the paper, and Dr.
Wang Liqiu from the School of Life Sciences, Sun Yat-sen University is the first author of the paper. Original link: Platemaker: Qijiang References 1.
Sunderland EM, Hu XC, Dassuncao C, Tokranov AK, Wagner CC, Allen JG .
A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects.
J Expo Sci Environ Epidemiol.
29, 131-47 (2019).
2.
Chang ET, Adami HO, Boffetta P , Wedner HJ, Mandel JS.
A critical review of perfluorooctanoate and perfluorooctanesulfonate exposure and immunological health conditions in humans.
Crit Rev Toxicol.
46, 279-331 (2016) 3.
Negri E, Metruccio F, Guercio V, Tosti L, Benfenati E, Bonzi R, et al.
Exposure to PFOA and PFOS and fetal growth: a critical merging of toxicological and epidemiological data.
Crit Rev Toxicol.
47, 482-508 (2017).
4.
Bevin E Blake, Susan M Pinney, Erin P Hines, Suzanne E Fenton, Kelly K Ferguson.
.
Associations Between Longitudinal Serum Perfluoroalkyl Substance (PFAS) Levels and Measures of Thyroid Hormone, Kidney Function, and Body Mass Index in the Fernald Community Cohort.
Environ Pollut.
242, 894-904 (2018).
5.
Qazi MR, Bogdanska J, Butenhoff JL, Nelson BD, DePierre JW, Abedi-Valugerdi M.
High-dose, short-term exposure of mice to perfluorooctanesulfonate (PFOS) or perfluorooctanoate (PFOA) affects the number of circulating neutrophils differently, but enhances the inflammatory responses of macrophages to lipopolysaccharide (LPS) in a similar fashion.
Toxicology.
262, 207-14 (2009).
6.
Wang G, Sun S, Wu X, Yang S, Wu Y, Zhao J, Zhang H, Chen W.
Intestinal environmental disorders associate with the tissue damages induced by perfluorooctane sulfonate exposure.
Ecotoxicol Environ Saf.
197:110590 (2020).
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