Protective Role of Interleukin-10 in Ozone-Induced Pulmonary Inflammation

Backus, Gillian S.; Howden, Reuben; Fostel, Jennifer; Bauer, Alison K.; Cho, Hye‐Youn; Marzec, Jacqui; Peden, David B.; Kleeberger, Steven R.

doi:10.1289/ehp.1002182

Cited by 38 publications

(24 citation statements)

References 47 publications

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“…1A–C), consistent with previous reports by ourselves and others [18], [22], [23], [41], [42]. Increases in BAL inflammatory cells were significantly reduced in TCRδ −/− versus WT mice after 48 (neutrophils) and 72 (neutrophils and macrophages) hours of exposure (Fig.…”

Section: Resultssupporting

confidence: 92%

γδ T Cells Are Required for Pulmonary IL-17A Expression after Ozone Exposure in Mice: Role of TNFα

Mathews¹,

Williams²,

Brand³

et al. 2014

PLoS ONE

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Ozone is an air pollutant that causes pulmonary symptoms. In mice, ozone exposure causes pulmonary injury and increases bronchoalveolar lavage macrophages and neutrophils. We have shown that IL-17A is important in the recruitment of neutrophils after subacute ozone exposure (0.3 ppm for 24–72 h). We hypothesized that γδ T cells are the main producers of IL-17A after subacute ozone. To explore this hypothesis we exposed wildtype mice and mice deficient in γδ T cells (TCRδ−/−) to ozone or room air. Ozone-induced increases in BAL macrophages and neutrophils were attenuated in TCRδ−/− mice. Ozone increased the number of γδ T cells in the lungs and increased pulmonary Il17a mRNA expression and the number of IL-17A+ CD45+ cells in the lungs and these effects were abolished in TCRδ−/− mice. Ozone-induced increases in factors downstream of IL-17A signaling, including G-CSF, IL-6, IP-10 and KC were also decreased in TCRδ−/− versus wildtype mice. Neutralization of IL-17A during ozone exposure in wildtype mice mimicked the effects of γδ T cell deficiency. TNFR2 deficiency and etanercept, a TNFα antagonist, also reduced ozone-induced increases in Il17a mRNA, IL-17A+ CD45+ cells and BAL G-CSF as well as BAL neutrophils. TNFR2 deficient mice also had decreased ozone-induced increases in Ccl20, a chemoattractant for IL-17A+ γδ T cells. Il17a mRNA and IL-17A+ γδ T cells were also lower in obese Cpefat versus lean WT mice exposed to subacute ozone, consistent with the reduced neutrophil recruitment observed in the obese mice. Taken together, our data indicate that pulmonary inflammation induced by subacute ozone requires γδ T cells and TNFα-dependent recruitment of IL-17A+ γδ T cells to the lung.

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Section: Resultssupporting

confidence: 92%

γδ T Cells Are Required for Pulmonary IL-17A Expression after Ozone Exposure in Mice: Role of TNFα

Mathews¹,

Williams²,

Brand³

et al. 2014

PLoS ONE

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“…In the present study we found that baseline IL-10 levels in sputum of allergic asthmatics were significantly decreased compared to normal volunteers (p=0.007), and there was a similar trend for difference with atopic non-asthmatics (p=0.09). Studies of IL-10 knockout mice indicate that IL-10 appears to be protective against O 3 -induced neutrophilic inflammation and NFkB activation54. Therefore, suppressed baseline IL-10 in our atopic asthmatic cohort may have contributed to increased pro-inflammatory cytokine production after O 3 exposure.…”

Section: Discussionmentioning

confidence: 83%

Atopic asthmatic subjects but not atopic subjects without asthma have enhanced inflammatory response to ozone

Hernández

Lay

Harris

et al. 2010

Journal of Allergy and Clinical Immunology

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Background Asthma is a known risk factor for acute ozone-associated respiratory disease. Ozone (O3) causes an immediate decrease in lung function and increased airway inflammation. The role of atopy and asthma in modulation of O3-induced inflammation has not been determined. Objective To determine if atopic status modulates O3 response phenotypes in humans. Methods Fifty volunteers (25 normal volunteers, 14 atopic non-asthmatics, 11 atopic asthmatics not requiring maintenance therapy) underwent a 0.4 ppm O3 exposure protocol. Ozone response was determined by changes in lung function and induced sputum composition, including airway inflammatory cell concentration, cell surface markers, cytokine and hyaluronic acid concentration. Results All cohorts experienced similar decreases in lung function post O3. Atopics and atopic asthmatics had increased sputum neutrophils and IL-8 after O3 exposure; levels did not significantly change in normal volunteers. Following O3 exposure, atopic asthmatics had significantly increased sputum IL-6 and IL-1 β, and airway macrophage TLR4, FceRI, and CD23 expression; levels in normal volunteers and atopic non-asthmatics showed no significant change. Atopic asthmatics had significantly decreased IL-10 at baseline compared to normal volunteers: IL-10 did not significantly change in any group with O3. All groups had similar levels of hyaluronic acid at baseline, with increased levels after O3 exposure in atopics and atopic asthmatics. Conclusion Atopic asthmatics have increased airway inflammatory responses to O3. Elevated TLR4 expression suggests a potential pathway through which O3 generates the inflammatory response in allergic asthmatics but not in atopics without asthma. Clinical Implications These observations suggest that mild atopic asthma confers increased risk for exacerbation of O3-induced lung disease through promoting an enhanced innate immune inflammatory response to O3.

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“…The studies reported here used a 72-h ozone exposure period to examine the impact of IL-6 on neutrophil recruitment. Differences in the kinetics of O 3 -induced pulmonary inflammation have been reported depending on the precise outcome indicator examined (5,6). Hence, it is conceivable that the IL-6-dependent SAA3/IL-17A/G-CSF-mediated neutrophil recruitment observed in Adipo Ϫ/Ϫ mice exposed to ozone, as outlined in Fig.…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice

Kasahara¹,

Kim

Mathews³

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24-72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin-deficient (Adipo(-/-)) mice. The IL-17/granulocyte colony-stimulating factor (G-CSF) axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo(-/-) mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 (Adipo(-/-)/IL-6(-/-)) and exposed them to ozone or air. In ozone-exposed mice, bronchoalveolar lavage (BAL) neutrophils, IL-6, and G-CSF, and pulmonary Il17a mRNA expression were greater in Adipo(-/-) vs. wild-type mice, but reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice. IL-17A(+) F4/80(+) cells and IL-17A(+) γδ T cells were also reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice exposed to ozone. Only BAL neutrophils were reduced in IL-6(-/-) vs. wild-type mice. In wild-type mice, IL-6 was expressed in Gr-1(+)F4/80(-)CD11c(-) cells, whereas in Adipo(-/-) mice F4/80(+)CD11c(+) cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 (Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo(-/-) vs. wild-type mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo(-/-) vs. wild-type mice but reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo(-/-) mice after ozone exposure and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A, and G-CSF.

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Protective Role of Interleukin-10 in Ozone-Induced Pulmonary Inflammation

Cited by 38 publications

References 47 publications

γδ T Cells Are Required for Pulmonary IL-17A Expression after Ozone Exposure in Mice: Role of TNFα

γδ T Cells Are Required for Pulmonary IL-17A Expression after Ozone Exposure in Mice: Role of TNFα

Atopic asthmatic subjects but not atopic subjects without asthma have enhanced inflammatory response to ozone

Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice

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