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Lack of autophagy induces steroid-resistant airway inflammation.

ABSTRACT: BACKGROUND:Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease. OBJECTIVE:We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma. METHODS:We developed CD11c-specific autophagy-related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of autophagy in asthmatic patients. RESULTS:For the first time, we found that deletion of the Atg5 gene specifically in CD11c(+) cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c(+) cells in wild-type mice. We further found that adoptive transfer of Atg5(-/-), but not wild-type, bone marrow-derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5(-/-) mice is glucocorticoid resistant and IL-17A dependent. CONCLUSION:Our results suggest that lack of autophagy in pulmonary CD11c(+) cells induces neutrophilic airway inflammation and hyperreactivity.

SUBMITTER: Suzuki Y

PROVIDER: S-EPMC4860134 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Lack of autophagy induces steroid-resistant airway inflammation.

Suzuki Yuzo Y Maazi Hadi H Sankaranarayanan Ishwarya I Lam Jonathan J Khoo Bryant B Soroosh Pejman P Barbers Richard G RG James Ou J-H JH Jung Jae U JU Akbari Omid O

The Journal of allergy and clinical immunology 20151114 5

<h4>Background</h4>Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease.<h4>Objective</h4>We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma.<h4>Methods</h4>We developed CD11c-specific autophagy-related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of ...[more]

PMID: 26589586

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Project description:BackgroundExacerbations of asthma are linked to significant decline in lung function and are often poorly controlled by corticosteroid treatment. Clinical investigations indicate that viral and bacterial infections play crucial roles in the onset of steroid-resistant inflammation and airways hyperresponsiveness (AHR) that are hallmark features of exacerbations. We have previously shown that interferon ? (IFN?) and lipopolysaccharide (LPS) cooperatively activate pulmonary macrophages and induce steroid-resistant airway inflammation and AHR in mouse models. Furthermore, we have established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation of asthma, which exhibits macrophage-dependent, steroid-resistant lung disease. Emerging evidence has demonstrated a key role for bromo- and extra-terminal (BET) proteins in the regulation of inflammatory gene expression in macrophages. We hypothesised that BET proteins may be involved in the regulation of AHR and airway inflammation in our steroid-resistant exacerbation models.Methodology/principal findingsWe investigated the effects of a BET inhibitor (I-BET-762) on the development of steroid-resistant AHR and airway inflammation in two mouse models. I-BET-762 administration decreased macrophage and neutrophil infiltration into the airways, and suppressed key inflammatory cytokines in both models. I-BET treatment also suppressed key inflammatory cytokines linked to the development of steroid-resistant inflammation such as monocyte chemoattractant protein 1 (MCP-1), keratinocyte-derived protein chemokine (KC), IFN?, and interleukin 27 (IL-27). Attenuation of inflammation was associated with suppression of AHR.Conclusions/significanceOur results suggest that BET proteins play an important role in the regulation of steroid-resistant exacerbations of airway inflammation and AHR. BET proteins may be potential targets for the development of future therapies to treat steroid-resistant inflammatory components of asthma.

Project description:Allergic airway inflammation is a chronic inflammatory condition resulting from uncontrolled immune responses to environmental antigens. While it is well-established that allergic immune responses exhibit a high degree of diversity, driven by primary effector cell types like eosinophils, neutrophils, or CD4 T cells with distinct effector signatures, the exact mechanisms responsible for such pathogenesis remain largely elusive. Foxp3+ regulatory T cells (Treg) is an indispensable immune regulator during chronic inflammation including allergic airway inflammation. Emerging evidence suggests that Tregs infiltrating inflamed tissues exhibit distinct phenotypes dependent on the specific tissue sites and can display significant heterogeneity and tissue residency. Whether diverse allergic inflammatory responses in the lung influences infiltrating Treg heterogeneity or Treg lung residency has not previously been explored. We employed an unbiased single-cell RNAseq approach to study lung-infiltrating Tregs in models of eosinophilic and neutrophilic airway inflammation models, in which Tregs are critical immune regulators of inflammation. We found that lung-infiltrating Tregs are highly heterogeneous and that Tregs displaying lung residency phenotypes are significantly different depending on the types of inflammation. Tregs expression of ST2, a receptor for alarmin cytokine IL-33, was predominantly induced by eosinophilic inflammation and by tissue residency. However, Treg-specific ST2 deficiency did not affect the development of eosinophilic allergic inflammation nor the generation of lung resident Tregs. These results uncover a striking heterogeneity among Tregs infiltrating the lungs during allergic airway inflammation. The results also indicate that varying types of inflammation may give rise to phenotypically distinct lung resident Tregs. Thus, the present study underscores a novel mechanism by which inflammatory environments may shape the composition of infiltrating Tregs, allowing them to regulate inflammatory responses through tissue-adapted mechanisms.

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Lack of autophagy induces steroid-resistant airway inflammation.

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Lack of autophagy induces steroid-resistant airway inflammation.

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