TLR4 Signaling Attenuates Ongoing Allergic Inflammation

Hollingsworth, John W.; Whitehead, Gregory S.; Lin, Kaifeng; Nakano, Hideki; Gunn, Michael D.; Schwartz, David A.; Cook, Donald N.

doi:10.4049/jimmunol.176.10.5856

Cited by 92 publications

(84 citation statements)

References 48 publications

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“…Eight-to twelve-week-old C57BL/6J mice (The Jackson Laboratory) were immunized and subjected to an OVA challenge as previously described (38). In brief, animals were immunized on days 0 and 7 by i.p.…”

Section: Methodsmentioning

confidence: 99%

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In utero supplementation with methyl donors enhances allergic airway disease in mice

Hollingsworth¹,

Maruoka²,

Boon³

et al. 2008

J. Clin. Invest.

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Asthma is a complex heritable disease that is increasing in prevalence and severity, particularly in developed countries such as the United States, where 11% of the population is affected. The contribution of environmental and genetic factors to this growing epidemic is currently not well understood. We developed the hypothesis, based on previous literature, that changes in DNA methylation resulting in aberrant gene transcription may enhance the risk of developing allergic airway disease. Our findings indicate that in mice, a maternal diet supplemented with methyl donors enhanced the severity of allergic airway disease that was inherited transgenerationally. Using a genomic approach, we discovered 82 gene-associated loci that were differentially methylated after in utero supplementation with a methyl-rich diet. These methylation changes were associated with decreased transcriptional activity and increased disease severity. Runt-related transcription factor 3 (Runx3), a gene known to negatively regulate allergic airway disease, was found to be excessively methylated, and Runx3 mRNA and protein levels were suppressed in progeny exposed in utero to a high-methylation diet. Moreover, treatment with a demethylating agent increased Runx3 gene transcription, further supporting our claim that a methyl-rich diet can affect methylation status and consequent transcriptional regulation. Our findings indicate that dietary factors can modify the heritable risk of allergic airway disease through epigenetic mechanisms during a vulnerable period of fetal development in mice.

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Section: Methodsmentioning

confidence: 99%

“…Whole-lung lavage was completed and cell differentials were determined, as previously described (38). Lavage cells were spun onto a glass slide using a cytocentrifuge (Cytospin 2; Shandon Southern) and stained using a Hemacolor (EMD).…”

Section: Methodsmentioning

confidence: 99%

In utero supplementation with methyl donors enhances allergic airway disease in mice

Hollingsworth¹,

Maruoka²,

Boon³

et al. 2008

J. Clin. Invest.

Self Cite

180

211

View full text Add to dashboard Cite

show abstract

“…Inhalation of bacterial endotoxin can contribute to the development and progression of occupational lung disease (23). Furthermore, inhaled LPS can modify allergic asthma (24,25) and cause severe inflammatory disease in both humans and mice (26 -28). Although this immediate inflammatory response plays an important role in host defense, uncontrolled inflammation can contribute to the progression of pulmonary (and systemic) disease (29).…”

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confidence: 99%

Ambient Ozone Primes Pulmonary Innate Immunity in Mice

Hollingsworth

Maruoka

et al. 2007

The Journal of Immunology

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Exposure to ozone in air pollution in urban environments is associated with increases in pulmonary-related hospitalizations and mortality. Because ozone also alters clearance of pulmonary bacterial pathogens, we hypothesized that inhalation of ozone modifies innate immunity in the lung. To address our hypothesis, we exposed C57BL/6J mice to either free air or ozone, and then subsequently challenged with an aerosol of Escherichia coli LPS. Pre-exposure to ozone resulted in enhanced airway hyperreactivity, higher concentrations of both total protein and proinflammatory cytokines in lung lavage fluid, enhanced LPS-mediated signaling in lung tissue, and higher concentrations of serum IL-6 following inhalation of LPS. However, pre-exposure to ozone dramatically reduced inflammatory cell accumulation to the lower airways in response to inhaled LPS. The reduced concentration of cells in the lower airways was associated with enhanced apoptosis of both lung macrophages and systemic circulating monocytes. Moreover, both flow cytometry and confocal microscopy indicate that inhaled ozone causes altered distribution of TLR4 on alveolar macrophages and enhanced functional response to endotoxin by macrophages. These observations indicate that ozone exposure increases both the pulmonary and the systemic biologic response to inhaled LPS by priming the innate immune system.

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“…Mice were sensitized on Days Ϫ13 and Ϫ7 by intraperitoneal injections of ovalbumin (Sigma, St. Louis, MO) complexed to alum as previously described (18). Beginning on Day 0, these mice were exposed for 30 minutes to an aerosol of 1% ovalbumin (Sigma) in LPS-free saline (Sigma) generated using an Ultra-Neb99 (DeVilbiss Healthcare, Somerset, PA).…”

Section: Ovalbumin Sensitization and Challengementioning

confidence: 99%

The Chemokine Receptor D6 Has Opposing Effects on Allergic Inflammation and Airway Reactivity

Whitehead

Wang²,

DeGraff³

et al. 2007

Am J Respir Crit Care Med

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Rationale: The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2 (Th2)-associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its pulmonary function is unknown. Objectives: This study tested whether D6 regulates pulmonary chemokine levels, inflammation, or airway responsiveness during allergen-induced airway disease. Methods: D6-deficient and genetically matched C57BL/6 mice were sensitized and challenged with ovalbumin. ELISA and flow cytometry were used to measure levels of cytokines and leukocytes, respectively. Mechanical ventilation was used to measure airway reactivity. Results: The ability of D6 to diminish chemokine levels in the lung was chemokine concentration dependent. CCL17 and CCL22 were abundant in the airway, and their levels were attenuated by D6 when they were within a defined concentration range. By contrast, airway concentrations of CCL3, CCL5, and CCL11 were low and unaffected by D6. Allergen-challenged D6-deficient mice had more dendritic cells, T cells, and eosinophils in the lung parenchyma and more eosinophils in the airway than similarly challenged C57BL/6 mice. By contrast, D6-deficient mice had reduced airway responses to methacholine compared with C57BL/6 mice. Thus, D6 has opposing effects on inflammation and airway reactivity. Conclusions: The ability of D6 to scavenge chemokines in the lung is dependent on chemokine concentration. The absence of D6 increases inflammation, but reduces airway reactivity. These findings suggest that inhibiting D6 function might be a novel means to attenuate airway responses in individuals with allergic asthma.Keywords: chemokines; lung; D6; allergic; transforming growth factor-␤ Allergic asthma is a disease characterized by pulmonary inflammation and reversible airflow obstruction. In allergic asthma, T-helper 2 (Th2) cells recognizing common airborne antigens produce the cytokines IL-4, IL-5, and IL-13, which can account for virtually all of the manifestations of asthma, including eosinophil mobilization and airway remodeling (1). In principle, an effective therapy for asthma would be to inhibit the development of such allergen-specific Th2 cells. However, individuals that present with asthma have already developed Th2 responses to aeroaller- The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2-associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its function is unknown. What This Study Adds to the FieldThe absence of D6 increases airway inflammation, but reduces airway reactivity. Inhibiting D6 might attenuate airway responses in individuals with asthma.

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TLR4 Signaling Attenuates Ongoing Allergic Inflammation

Cited by 92 publications

References 48 publications

In utero supplementation with methyl donors enhances allergic airway disease in mice

In utero supplementation with methyl donors enhances allergic airway disease in mice

Ambient Ozone Primes Pulmonary Innate Immunity in Mice

The Chemokine Receptor D6 Has Opposing Effects on Allergic Inflammation and Airway Reactivity

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