Dataset Information

Chitinase 3-like 1 protein plays a critical role in respiratory syncytial virus-induced airway inflammation.

ABSTRACT:

Background

Chitinase 3-like 1 protein (CHI3L1) (YKL-40 in humans and breast regression protein [BRP]-39 in mice) is required for optimal allergen sensitization and Th2 inflammation in various chronic inflammatory diseases including asthma. However, the role of CHI3L1 in airway inflammation induced by respiratory viruses has not been investigated. The aim of this study was to investigate the relationship between CHI3L1 and airway inflammation caused by respiratory syncytial virus (RSV) infection.

Methods

We measured YKL-40 levels in human nasopharyngeal aspirate (NPA) from hospitalized children presenting with acute respiratory symptoms. Wild-type (WT) and BRP-39 knockout (KO) C57BL/6 mice were inoculated with live RSV (A2 strain). Bronchoalveolar lavage fluid and lung tissue samples were obtained on day 7 after inoculation to assess lung inflammation, airway reactivity, and expression of cytokines and BRP-39.

Results

In human subjects, YKL-40 and IL-13 levels in NPA were higher in children with RSV infection than in control subjects. Expression of BRP-39 and Th2 cytokines, IL-13 in particular, was increased following RSV infection in mice. Airway inflammation caused by RSV infection was reduced in BRP-39 KO mice as compared to WT mice. Th2 cytokine levels were not increased in the lungs of RSV-infected BRP-39 KO mice. BRP-39 regulated M2 macrophage activation in RSV-infected mice. Additionally, treatment with anti-CHI3L1 antibody attenuated airway inflammation and Th2 cytokine production in RSV-infected WT mice.

Conclusion

These findings suggest that CHI3L1 could contribute to airway inflammation induced by RSV infection. CHI3L1 could be a potential therapeutic candidate for attenuating Th2-associated immunopathology during RSV infection.

SUBMITTER: Kim MJ

PROVIDER: S-EPMC7159489 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Chitinase 3-like 1 protein plays a critical role in respiratory syncytial virus-induced airway inflammation.

Kim Min Jung MJ Shim Doo Hee DH Cha Hye-Ran HR Moon Kuk-Young KY Yang Chang Mo CM Hwang Su Jin SJ Kim Kyung Won KW Park Jeon Han JH Lee Chun Geun CG Elias Jack A JA Sohn Myung Hyun MH Lee Jae Myun JM

Allergy 20181204 4

<h4>Background</h4>Chitinase 3-like 1 protein (CHI3L1) (YKL-40 in humans and breast regression protein [BRP]-39 in mice) is required for optimal allergen sensitization and Th2 inflammation in various chronic inflammatory diseases including asthma. However, the role of CHI3L1 in airway inflammation induced by respiratory viruses has not been investigated. The aim of this study was to investigate the relationship between CHI3L1 and airway inflammation caused by respiratory syncytial virus (RSV) in ...[more]

PMID: 30402955

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Project description:Lower respiratory tract infection with respiratory syncytial virus (RSV) produces profound inflammation. Despite an understanding of the role of adaptive immunity in RSV infection, the identity of the major sentinel cells initially triggering inflammation is controversial. Here we evaluate the role of nonciliated secretoglobin (Scgb1a1)-expressing bronchiolar epithelial cells in RSV infection. Mice expressing a tamoxifen (TMX)-inducible Cre recombinase-estrogen receptor fusion protein (CreERTM) knocked into the Scgb1a1 locus were crossed with mice that harbor a RelA conditional allele (RelAfl ), with loxP sites flanking exons 5 to 8 of the Rel homology domain. The Scgb1a1CreERTM/+ × RelAfl/fl mouse is a RelA conditional knockout (RelACKO) of a nonciliated epithelial cell population enriched in the small bronchioles. TMX-treated RelACKO mice have reduced pulmonary neutrophilic infiltration and impaired expression and secretion of NF-?B-dependent cytokines in response to RSV. In addition, RelACKO mice had reduced expression levels of interferon (IFN) regulatory factor 1/7 (IRF1/7) and retinoic acid-inducible gene I (RIG-I), components of the mucosal IFN positive-feedback loop. We demonstrate that RSV replication induces RelA to complex with bromodomain-containing protein 4 (BRD4), a cofactor required for RNA polymerase II (Pol II) phosphorylation, activating the atypical histone acetyltransferase (HAT) activity of BRD4 required for phospho-Ser2 Pol II formation, histone H3K122 acetylation, and cytokine secretion in vitro and in vivo TMX-treated RelACKO mice have less weight loss and reduced airway obstruction/hyperreactivity yet similar levels of IFN-? production despite higher levels of virus production. These data indicate that the nonciliated Scgb1a1-expressing epithelium is a major innate sensor for restricting RSV infection by mediating neutrophilic inflammation and chemokine and mucosal IFN production via the RelA-BRD4 pathway.IMPORTANCE RSV infection is the most common cause of infant hospitalizations in the United States, resulting in 2.1 million children annually requiring medical attention. RSV primarily infects nasal epithelial cells, spreading distally to produce severe lower respiratory tract infections. Our study examines the role of a nonciliated respiratory epithelial cell population in RSV infection. We genetically engineered a mouse that can be selectively depleted of the NF-?B/RelA transcription factor in this subset of epithelial cells. These mice show an impaired activation of the bromodomain-containing protein 4 (BRD4) coactivator, resulting in reduced cytokine expression and neutrophilic inflammation. During the course of RSV infection, epithelial RelA-depleted mice have reduced disease scores and airway hyperreactivity yet increased levels of virus replication. We conclude that RelA-BRD4 signaling in nonciliated bronchiolar epithelial cells mediates neutrophilic airway inflammation and disease severity. This complex is an attractive target to reduce the severity of infection.

Dataset Information

Chitinase 3-like 1 protein plays a critical role in respiratory syncytial virus-induced airway inflammation.

Background

Methods

Results

Conclusion

Publications

Chitinase 3-like 1 protein plays a critical role in respiratory syncytial virus-induced airway inflammation.

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