Ozone Inhalation Promotes CX3CR1-Dependent Maturation of Resident Lung Macrophages That Limit Oxidative Stress and Inflammation

Tighe, Robert; Li, Zhuowei; Potts, Erin N.; Frush, Sarah; Liu, Ningshan; Gunn, Michael D.; Foster, W. Michael; Noble, Paul W.; Hollingsworth, John W.

doi:10.4049/jimmunol.1101312

Cited by 38 publications

(33 citation statements)

References 57 publications

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“…Evidence suggests that these diverse activities are mediated by distinct subpopulations of macrophages that appear sequentially in tissues in response to injury (Byers and Holtzman, 2011; Laskin et al , 2011). Consistent with this notion are previous reports that, initially, proinflammatory/cytotoxic M1 macrophages, and subsequently anti-inflammatory/wound repair M2 macrophages, accumulate in the lung after ozone, and that these cells contribute to tissue injury and repair, respectively (Pendino et al , 1994; Koike et al , 1998; Hollingsworth et al , 2007; Tighe et al , 2011; Sunil et al , 2012). The present studies identify a novel population of macrophages in the lung after exposure to ozone that is important in promoting proinflammatory signaling and tissue injury.…”

Section: Discussionsupporting

confidence: 83%

Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3

Sunil

Francis

Vayas

et al. 2015

Toxicology and Applied Pharmacology

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Macrophages play a dual role in ozone toxicity, contributing to both pro- and anti-inflammatory processes. Galectin-3 (Gal-3) is a lectin known to regulate macrophage activity. Herein, we analyzed the role of Gal-3 in the response of lung macrophages to ozone. Bronchoalveolar lavage (BAL) and lung tissue were collected 24–72 h after exposure (3 h) of WT and Gal-3−/− mice to air or 0.8 ppm ozone. In WT mice, ozone inhalation resulted in increased numbers of proinflammatory (Gal-3+, iNOS+) and anti-inflammatory (MR-1+) macrophages in the lungs. While accumulation of iNOS+ macrophages was attenuated in Gal-3−/− mice, increased numbers of enlarged MR-1+ macrophages were noted. This correlated with increased numbers of macrophages in BAL. Flow cytometric analysis showed that these cells were CD11b+ and consisted mainly (>97%) mature (F4/80+CD11c+) proinflammatory (Ly6G−Ly6Chi) and anti-inflammatory (Ly6G−Ly6Clo) macrophages. Increases in both macrophage subpopulations were observed following ozone inhalation. Loss of Gal-3 resulted in a decrease in Ly6Chi macrophages, with no effect on Ly6Clo macrophages. CD11b+Ly6G+Ly6C+ granulocytic (G) and monocytic (M) myeloid derived suppressor cells (MDSC) were also identified in the lung after ozone. In Gal-3−/− mice, the response of G-MDSC to ozone was attenuated, while the response of M-MDSC was heightened. Changes in inflammatory cell populations in the lung of ozone treated Gal-3−/− mice were correlated with reduced tissue injury as measured by cytochrome b5 expression. These data demonstrate that Gal-3 plays a role in promoting proinflammatory macrophage accumulation and toxicity in the lung following ozone exposure.

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Section: Discussionsupporting

confidence: 83%

Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3

Sunil

Francis

Vayas

et al. 2015

Toxicology and Applied Pharmacology

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“…CD45 + BAL cells fell within one of four distinct populations on a Gr-1/CD11c plot. The Gr-1 − CD11c − population in the BALF consisted of lymphocytes, Gr-1 + CD11c − of neutrophils, Gr-1 lo/− CD11c hi and Gr-1 + CD11c hi of macrophages [17], [19]. At baseline (no exposures), within the CD45 + population of cells, the major cell types were macrophages (Gr-1 lo/− CD11c hi and Gr-1 + CD11c hi ), accounting for 95% of CD45 + cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Vitamin D Deficiency Causes Defective Resistance to Aspergillus fumigatus in Mice via Aggravated and Sustained Inflammation

Cao

et al. 2014

PLoS ONE

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BackgroundVitamin D plays an important role in pulmonary resistance and immunity, and its deficiency has been linked to various respiratory infections. Little is known about the effect of vitamin D deficiency on host pulmonary defense to Aspergillus fumigatus (A. fumigatus).MethodsMice raised on vitamin D sufficient or deficient diets were infected intratracheally with A. fumigatus conidia. Mortality, fungal growth, weight loss and lung histology were monitored. Alveolar macrophages (AMs) were stimulated with A. fumigatus conidia in vitro. The kinetics of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), chemokines (CXCL1, CCL3), and pattern recognition receptors (Toll-like receptor [TLR] 2, TLR 4 and dectin-1) expression in the lungs and AMs were measured.ResultsUpon A. fumigatus infection, vitamin D deficient mice showed higher mortality, greater fungal load, and more weight loss than its sufficient counterparts. Vitamin D deficient mice demonstrated aggravated and prolonged histological evidence of lung inflammation as well as enhanced BAL cell counts, dominated by neutrophils after A. fumigatus inoculation. Increased basal levels of pro-inflammatory cytokines in the lungs and AMs from naïve vitamin D deficient mice were observed. Upon A. fumigatus exposure, vitamin D deficiency led to enhanced and sustained expression of TNF-α, IL-1β, IL-6, CXCL1 and CCL3 both in vivo and in vitro. Up-regulation of TLR2, TLR4 and dectin-1was observed in the lungs and AMs from vitamin D deficient mice both at baseline and after A. fumigatus exposure.ConclusionsVitamin D deficiency causes defective pulmonary resistance to A. fumigatus in mice, possibly by the enhanced basal expression of pattern recognition receptors and pro-inflammatory cytokines, which induced excessive inflammatory response in response to A. fumigatus challenge.

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“…However, monocytes also express Gr-1 on their surface (19). A similar but not identical population of Gr-1 ϩ macrophages was shown to be induced by acute ozone and have higher expression of CX3CR1 and MARCO compared with alveolar macrophages (55). In recent years, a new granulocytic population have been described as CD11b ϩ Gr-1 ϩ F4/80 Ϫ Ly-6c int Ly-6G hi with anti-inflammatory role in inflammation induced by tumor, also known as granulocytic myeloid-derived suppressor cells (g-MDSC or MDSC) (8,48,66).…”

Section: Discussionmentioning

confidence: 96%

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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Ozone Inhalation Promotes CX3CR1-Dependent Maturation of Resident Lung Macrophages That Limit Oxidative Stress and Inflammation

Cited by 38 publications

References 57 publications

Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3

Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3

Vitamin D Deficiency Causes Defective Resistance to Aspergillus fumigatus in Mice via Aggravated and Sustained Inflammation

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

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