Particulate matter of 2.5 μm or less in diameter disturbs the balance of T(H)17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model.

Epidemiologic evidence suggests that exposure to particulate matter of 2.5 μm or less in diameter (PM2.5) aggravates asthma. We sought to investigate the underlying mechanisms between PM2.5 exposure and asthma severity. The relationship between PM2.5 exposure and asthma severity was investigated in an asthma model with CD4+ T cell-specific aryl hydrocarbon receptor (AhR)-null mice. Effects of PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on differentiation of TH17/regulatory T (Treg) cells were investigated by using flow cytometry and quantitative RT-PCR. Mechanisms were investigated by using mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing, and glycolysis rates. PM2.5 impaired differentiation of Treg cells, promoted differentiation of TH17 cells, and aggravated asthma in an AhR-dependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of TH17 cells by upregulating hypoxia-inducible factor 1α expression and enhancing glycolysis through AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase 1 (Got1) expression through AhRs and accumulation of 2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase 2 activity, resulting in hypermethylation in the forkhead box P3 locus and impaired differentiation of Treg cells. A GOT1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of TH17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on TH17/Treg cell imbalance were noted in human T cells, and in a case-control design PAH exposure appeared to be a potential risk factor for asthma. The AhR-hypoxia-inducible factor 1α and AhR-GOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of TH17/Treg cells.

Sun L ，Fu J ，Lin SH ，Sun JL ，Xia L ，Lin CH ，Liu L ，Zhang C ，Yang L ，Xue P ，Wang X ，Huang S ，Han X ，Chen HL ，Huang MS ，Zhang X ，Huang SK ，Zhou Y ... -  《-》

Traffic-related PM(2.5) and diverse constituents disturb the balance of Th17/Treg cells by STAT3/RORγt-STAT5/Foxp3 signaling pathway in a rat model of asthma.

Water-soluble ions (WSI) and organic extract (OE) in traffic-related particulate matter with aerodynamic diameters ≤ 2.5 μm (TRPM2.5) are potential risk factors for asthma exacerbation. Although CD4+ T lymphocytes mediated immune response is involved in the pathogenesis of asthma, the effect of WSI-TRPM2.5 and OE-TRPM2.5 on the balance of Th17/Treg cells in asthma remains poorly understood. In this study, the ovalbumin (OVA)-sensitized rats were repeatedly exposure to TRPM2.5 (3 mg/kg·bw), WSI-TRPM2.5 (1.8 mg/kg·bw, 7.2 mg/kg·bw) and OE-TRPM2.5 (0.6 mg/kg·bw, 2.4 mg/kg·bw) every three days for five times. The inflammation response and hyperemia edema were observed in the lung and trachea tissues. DNA methylation levels of STAT3 and RORγt genes in rats with WSI-TRPM2.5 and OE-TRPM2.5 treatment were decreased. DNA methylation level in STAT5 gene tended to decrease, with no change observed on Foxp3 expression. WSI-TRPM2.5 and OE-TRPM2.5 enhanced the mRNA and protein expression of STAT3 and RORγt while inhibited the expression of STAT5 and Foxp3, which may contribute to the imbalance of Th17/Treg cells (P < 0.05). More importantly, recovered balance of Th17/Treg cell subsets, upregulated p-STAT5 and Foxp3 expression and reduced p-STAT3 and RORγt levels were observed after 5-Aza treatment. Our results demonstrate that the STAT3/RORγt-STAT5/Foxp3 signaling pathway is involved in asthma exacerbation induced by WSI-TRPM2.5 and OE-TRPM2.5 through disrupting the balance of Th17/Treg cells. The alteration of DNA methylation of STAT3, STAT5, and RORγt genes may be involved in asthma exacerbation as well.

Wang C ，Wang D ，Zhao H ，Wang J ，Liu N ，Shi H ，Tian J ，Wang X ，Zhang Z ... -  《-》

Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro.

O'Driscoll CA ，Gallo ME ，Hoffmann EJ ，Fechner JH ，Schauer JJ ，Bradfield CA ，Mezrich JD ... -  《PLoS One》

Association between particulate matter containing EPFRs and neutrophilic asthma through AhR and Th17.

Epidemiological data associate high levels of combustion-derived particulate matter (PM) with deleterious respiratory outcomes, but the mechanism underlying those outcomes remains elusive. It has been acknowledged by the World Health Organization that PM exposure contributes to more than 4.2 million all-cause mortalities worldwide each year. Current literature demonstrates that PM exacerbates respiratory diseases, impairs lung function, results in chronic respiratory illnesses, and is associated with increased mortality. The proposed mechanisms revolve around oxidative stress and inflammation promoting pulmonary physiological remodeling. However, our previous data found that PM is capable of inducing T helper cell 17 (Th17) immune responses via aryl hydrocarbon receptor (Ahr) activation, which was associated with neutrophilic invasion characteristic of steroid insensitive asthma. In the present study, we utilized a combination of microarray and single cell RNA sequencing data to analyze the immunological landscape in mouse lungs following acute exposure to combustion derived particulate matter. We present data that suggest epithelial cells produce specific cytokines in the aryl hydrocarbon receptor (Ahr) pathway that inform dendritic cells to initiate the production of pathogenic T helper (eTh17) cells. Using single-cell RNA sequencing analysis, we observed that upon exposure epithelial cells acquire a transcriptomic profile indicative of increased Il-17 signaling, Ahr activation, Egfr signaling, and T cell receptor and co-stimulatory signaling pathways. Epithelial cells further showed, Ahr activation is brought on by Ahr/ARNT nuclear translocation and activation of tyrosine kinase c-src, Egfr, and subsequently Erk1/2 pathways. Collectively, our data corroborates that PM initiates an eTh17 specific inflammatory response causing neutrophilic asthma through pathways in epithelial, dendritic, and T cells that promote eTh17 differentiation during initial PM exposure.

Harding JN ，Gross M ，Patel V ，Potter S ，Cormier SA ... -  《RESPIRATORY RESEARCH》

Indeno[1,2,3-cd]pyrene enhances the sensitivity of airway epithelial cells to ferroptosis and aggravates asthma.

Particulate matter of aerodynamic diameter ≤2.5 μm (PM2.5) exposure induces oxidative stress in lung tissues. Ferroptosis is a form of regulated cell death based on oxidative damage and lipid peroxidation. Whether PM2.5 exposure-induced oxidative stress can promote ferroptosis to aggravate asthma is not known. To investigate if PM2.5 exposure induces oxidative stress to promote ferroptosis and influence asthma development, a cockroach extract-induced asthma model in mice was used for in vivo studies. Airway epithelial cell (AEC) ferroptosis was detected by assays (CCK8, malonaldehyde, and 4-hydroxynonenal). Molecular mechanisms were investigated by real-time reverse transcription-quantitative polymerase chain reaction, western blotting, flow cytometry, liquid chromatography-tandem mass spectrometry, and chromatin immunoprecipitation. We found that exposure to PM2.5 and Indeno[1,2,3-cd] pyrene (IP; one of the prominent absorbed polycyclic aromatic hydrocarbons in PM2.5) enhanced the sensitivity of AECs to ferroptosis to aggravate asthma, whereas ferroptosis inhibitors and cytosolic phospholipase A2 (cPLA2) inhibitors reversed this augmented inflammatory response in mice suffering from asthma. IP treatment enhanced cPLA2 expression/activation through aryl hydrocarbon receptor (AhR) genomic and non-genomic pathways, resulting in arachidonic-acid release to promote the sensitivity of AECs to ferroptosis. IP exposure enhanced the release of leukotriene-B4 from lung macrophages, resulting in enhanced expression of acyl-coA synthetase long chain family member4 (ACSL4) and the sensitivity of AECs to ferroptosis. This finding suggests that exposure to PM2.5 and IP promote ferroptosis sensitivity in AECs to aggravate asthma, which may provide new targets for the prevention and treatment of asthma.

Yu H ，Zhang C ，Pan H ，Gao X ，Wang X ，Xiao W ，Yan S ，Gao Y ，Fu J ，Zhou Y ... -  《-》