Involvement of TLR2 and TLR4 and Th1/Th2 shift in inflammatory responses induced by fine ambient particulate matter in mice

Zhao, Can; Liao, Jiping; Chu, Weili; Wang, Suxia; Yang, Tongsheng; Tao, Yong; Wang, Guangfa

doi:10.3109/08958378.2012.731093

Cited by 87 publications

(57 citation statements)

References 42 publications

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“…Here, we confirmed that DEPs triggers TLR4, and the NFκB pathway in both pineal microglia and alveolar macrophages. As previously observed following LPS exposure, the DEP‐induced blockade of microglial TNF production triggered TNFR1 in pinealocytes, blocking pineal melatonin synthesis.…”

Section: Discussionsupporting

confidence: 74%

Immune‐pineal axis protects rat lungs exposed to polluted air

Carvalho-Sousa

Pereira

Kinker

et al. 2020

Journal of Pineal Research

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Environmental pollution in the form of particulate matter <2.5 μm (PM2.5) is a major risk factor for diseases such as lung cancer, chronic respiratory infections, and major cardiovascular diseases. Our goal was to show that PM2.5 eliciting a proinflammatory response activates the immune‐pineal axis, reducing the pineal synthesis and increasing the extrapineal synthesis of melatonin. Herein, we report that the exposure of rats to polluted air for 6 hours reduced nocturnal plasma melatonin levels and increased lung melatonin levels. Melatonin synthesis in the lung reduced lipid peroxidation and increased PM2.5 engulfment and cell viability by activating high‐affinity melatonin receptors. Diesel exhaust particles (DEPs) promoted the synthesis of melatonin in a cultured cell line (RAW 264.7 cells) and rat alveolar macrophages via the expression of the gene encoding for AANAT through a mechanism dependent on activation of the NFκB pathway. Expression of the genes encoding AANAT, MT1, and MT2 was negatively correlated with cellular necroptosis, as disclosed by analysis of Gene Expression Omnibus (GEO) microarray data from the human alveolar macrophages of nonsmoking subjects. The enrichment score for antioxidant genes obtained from lung gene expression data (GTEx) was significantly correlated with the levels of AANAT and MT1 but not the MT2 melatonin receptor. Collectively, these data provide a systemic and mechanistic rationale for coordination of the pineal and extrapineal synthesis of melatonin by a standard damage‐associated stimulus, which activates the immune‐pineal axis and provides a new framework for understanding the effects of air pollution on lung diseases.

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Section: Discussionsupporting

confidence: 74%

Immune‐pineal axis protects rat lungs exposed to polluted air

Carvalho-Sousa

Pereira

Kinker

et al. 2020

Journal of Pineal Research

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“…35 This fraction was chosen because the size of <2.5 μm in diameter allows the particles to travel via the airways into the alveoli. The dose chosen was at half the concentration of the dose reported to induce significant airway inflammation using PM 2.5 sampled in New York City, 35 Beijing, 36 and Baltimore. Antigen immunization and exposure to antigen and PM Animals were primed and challenged with antigen as described elsewhere 17,18 and schematically presented in Figure 2A.…”

Section: Urban Pm 18mentioning

confidence: 99%

Interleukin 13– and Interleukin 17A–Induced Pulmonary Hypertension Phenotype Due to Inhalation of Antigen and Fine Particles from Air Pollution

et al. 2014

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Pulmonary hypertension has a marked detrimental effect on quality of life and life expectancy. In a mouse model of antigen-induced pulmonary arterial remodeling, we have recently shown that coexposure to urban ambient particulate matter (PM) significantly increased the thickening of the pulmonary arteries and also resulted in significantly increased right ventricular systolic pressures. Here we interrogate the mechanism and show that combined neutralization of interleukin 13 (IL-13) and IL-17A significantly ameliorated the increase in right ventricular systolic pressure, the circumferential muscularization of pulmonary arteries, and the molecular change in the right ventricle. Surprisingly, our data revealed a protective role of IL-17A for the antigen-and PM-induced severe thickening of pulmonary arteries. This protection was due to the inhibition of the effects of IL-13, which drove this response, and the expression of metalloelastase and resistin-like molecule α. However, the latter was redundant for the arterial thickening response. Anti-IL-13 exacerbated airway neutrophilia, which was due to a resulting excess effect of IL-17A, confirming concurrent cross inhibition of IL-13-and IL-17A-dependent responses in the lungs of animals exposed to antigen and PM. Our experiments also identified IL-13/IL-17A-independent molecular reprogramming in the lungs induced by exposure to antigen and PM, which indicates a risk for arterial remodeling and protection from arterial constriction. Our study points to IL-13-and IL-17A-coinduced inflammation as a new template for biomarkers and therapeutic targeting for the management of immune response-induced pulmonary hypertension.

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“…The dose of PM2.5 that we used was at half the concentration of the dose reported to induce significant airway inflammation using PM2.5 sampled in New York City [38], Beijing [39], and Baltimore [40]. When given without OVA, PM2.5 at the 25 μg/50 μL dose did not elicit significant airway inflammation or vascular remodeling [7].…”

Section: Methodsmentioning

confidence: 99%

Elevated microRNA-135a is associated with pulmonary arterial hypertension in experimental mouse model

Lee

Park

2017

Oncotarget

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Multiple causes are associated with the complex mechanism of pathogenesis of pulmonary arterial hypertension (PAH), but the molecular pathway in the pathogenesis of PAH is still insufficiently understood. In this study, we investigated epigenetic changes that cause PAH induced by exposure to combined Th2 antigen (Ovalbumin, OVA) and urban particulate matter (PM) in mice. To address that, we focused on the epigenetic mechanism, linked to microRNA (miR)-135a. We found that miR-135a levels were significantly increased, and levels of bone morphogenetic protein receptor type II (BMPR2) which is the target of miR-135a, were significantly decreased in this experimental PAH mouse model. Therefore to evaluate the role of miR-135a, we injected AntagomiR-135a into this mouse model. AntagomiR-135a injected mice showed decreased right ventricular systolic pressures (RVSPs), right ventricular hypertrophy (RVH), and the percentage of severely thickened pulmonary arteries compared to control scrambled miRNA injected mice. Both mRNA and protein expression of BMPR2 were recovered in the AntagomiR-135a injected mice compared to control mice. Our study understands if miR-135a could serve as a biomarker helping to manage PAH. The blocking of miR-135a could lead to new therapeutic modalities to alleviate exacerbation of PAH caused by exposure to Th2 antigen and urban air pollution.

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Involvement of TLR2 and TLR4 and Th1/Th2 shift in inflammatory responses induced by fine ambient particulate matter in mice

Cited by 87 publications

References 42 publications

Immune‐pineal axis protects rat lungs exposed to polluted air

Immune‐pineal axis protects rat lungs exposed to polluted air

Interleukin 13– and Interleukin 17A–Induced Pulmonary Hypertension Phenotype Due to Inhalation of Antigen and Fine Particles from Air Pollution

Elevated microRNA-135a is associated with pulmonary arterial hypertension in experimental mouse model

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