Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma

Hong, Jun Young; Chung, Yutein; Steenrod, Jessica; Chen, Qiang; Lei, Jing; Comstock, Adam T.; Goldsmith, Adam M.; Bentley, J. Kelley; Sajjan, Uma S.; Hershenson, Marc B.

doi:10.1186/1465-9921-15-63

Cited by 43 publications

(38 citation statements)

References 67 publications

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“…Consistent with this, peripheral blood monocytes isolated from children undergoing viral-induced asthma exacerbations had elevated expression of alternatively activated macrophage signature genes (33). We have recently shown that, in the context of OVA sensitization and challenge, IL-4 receptor activation is required for M2 polarization of lung macrophages (34). Levels of the IL-4 receptor ligands IL-4 and IL-13 are likely to be enriched in the lungs of OVA-sensitized, RV-infected mice, consistent with intrapulmonary polarization.…”

Section: Original Researchsupporting

confidence: 62%

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

Chung¹,

Hong

Lei³

et al. 2015

Am J Respir Cell Mol Biol

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Rhinovirus (RV) causes asthma exacerbations. Previously, we showed that adherent bronchoalveolar cells from allergen-treated mice produce IL-13 when stimulated with RV ex vivo, implicating cells of the monocyte/macrophage lineage in viral-induced airway inflammation. In this study, we hypothesized that RV infection of allergen-treated mice results in IL-13 production by CD11b1 exudative macrophages in vivo. We sensitized and challenged BALB/c mice with ovalbumin (OVA), after which mice were inoculated with RV or sham HeLa cell lysate. After 1 day, lungs were harvested, and cell suspensions were analyzed by flow cytometry. We repeated this process in IL-13 reporter mice, CD11b-DTR mice in which diphtheria toxin selectively depletes CD11b1 cells, and chemokine receptor 2 (CCR2) null mice. We found that lungs of mice infected with RV alone showed increases in CD451, CD681, F4/801, Ly6C1, and CD11b high cells, indicating an influx of inflammatory monocytes and exudative macrophages. The combination of OVA and RV had synergistic effects on the exudative macrophage number. However, CD11b1 cells from OVA-treated, RV-infected mice showed M2 polarization, including expression of CD206 and CD301 and production of IL-13. Similar results were obtained in IL-13 reporter mice. Diphtheria toxin depleted CD11b1, IL-13-producing cells in OVA-treated, RV-infected, CD11b-DTR mice, decreasing airway inflammation and responsiveness. CD11b1, Ly6C1 cells were reduced in CCR2 knockout mice. We conclude that, in contrast to naive mice, RV infection of mice with allergic airways disease induces an influx of IL-13-producing CD11b1 exudative macrophages bearing M2 macrophage markers. This finding further implicates alternatively activated macrophages in RV-induced asthma exacerbations.

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Section: Original Researchsupporting

confidence: 62%

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

Chung¹,

Hong

Lei³

et al. 2015

Am J Respir Cell Mol Biol

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“…Increased macrophage numbers have been occasionally reported in models of asthma exacerbation [33,35,36]. It has been shown that after rhinovirus infection, alternatively activated (M2) airway macrophages can release type 2 cytokines, particularly IL-13, contributing to a Th2-exacerbated phenotype [37,38]. However, in our model, IL-13 is not increased and does not seem to play a role in the exacerbation.…”

Section: Discussioncontrasting

confidence: 54%

Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma

et al. 2015

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RNA viruses are a major cause of respiratory infections and are known to exacerbate asthma and other respiratory diseases. Our aim was to test the ability of poly(I:C) (polyinosinic:polycytidylic acid), a viral surrogate, to elicit exacerbation in a model of severe asthma driven by HDM (house dust mite) in FCA (Freund's complete adjuvant). Poly(I:C) was administered intranasally around the HDM challenge in FCA-HDM-sensitized animals. Changes in AHR (airway hyperresponsiveness), BALF (bronchoalveolar lavage fluid) inflammatory infiltrate, HDM-specific immunoglobulins and cytokine/chemokine release were evaluated at different points after the challenge. The effect of oral dexamethasone was also assessed. Exacerbation was achieved when poly(I:C) was administered 24 h before the HDM challenge and was characterized by enhanced AHR and an increase in the numbers of neutrophils, macrophages and lymphocytes in the BALF. Th1, Th2 and Th17 cytokines were also elevated at different time points after the challenge. Peribronchial and alveolar inflammation in lung tissue were also augmented. AHR and inflammatory infiltration showed reduced sensitivity to dexamethasone treatment. We have set up a model that mimics key aspects of viral exacerbation in a corticosteroid-refractory asthmatic phenotype which could be used to evaluate new therapies for this condition.

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“…The binding sites of STAT6 have been found in the target regions of a variety of IL-4-mediated genes, including CD23 (Cooper et al, 2012), IL-4R (Jenkins et al, 2013), eotaxin-1 (Waddell et al, 2013), eotaxin-3 (Nakayama et al, 2010), FIZZ1 (Dasgupta et al, 2011), and in Ig germline e (Lu et al, 2007) promoters. Recently, IL-4-driven STAT6 constitutive activation has been found in various diseases, such as allergy (Hong et al, 2014), tumors (Cheah et al, 2014;Creytens et al, in press;Koelsche et al, 2014), and lymphoproliferative disorders (Rawal et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

Wang

Duan

et al. 2015

The Anatomical Record

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IL-4 activates STAT6 and causes the subsequent up-regulation of Ig heavy chain germline Ige via chromatin remodeling involved in B lymphocytes development. STAT6 acts as a molecular switch to regulate the higher-order chromatin remodeling via dynamically orchestrating co-activators (CBP/Tudor-SN) and co-repressors (HDAC1/PSF). Here, we demonstrated that STAT6/Tudor-SN/PSF form a complex, balancing the acetylation and deacetylation states to co-regulate IL-4/STAT6 gene transcription. In addition, we confirmed that IL-4 treatment increased the HATs activity in Ramos cells. As "active" markers, the expression of H3K9ac and H3K27ac increased after treatment with IL-4. However, transcriptional repressors such as H3K9me3 and H3K27me3 decreased in response to IL-4 stimulation. Moreover, IL-4 treatment enhanced H3 acetylation at the Ige promoter regions. Our results revealed that the Ige gene transcription is regulated by histone modifications in the IL-4/STAT6 pathway. The study will provide novel insights into the pathogenesis of allergic diseases.

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Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma

Cited by 43 publications

References 67 publications

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

Rhinovirus Infection Induces Interleukin-13 Production from CD11b-Positive, M2-Polarized Exudative Macrophages

Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

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