Asthma and lower airway disease
Role of C/EBP homologous protein and endoplasmic reticulum stress in asthma exacerbation by regulating the IL-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4 receptor α positive feedback loop in M2 macrophages

https://doi.org/10.1016/j.jaci.2017.01.024Get rights and content

Background

C/EBP homologous protein (Chop), a marker of endoplasmic reticulum (ER) stress, exhibits aberrant expression patterns during asthma development. However, its exact role in asthma pathogenesis is not fully understood.

Objectives

We aimed to determine the function and mechanism of Chop in the pathogenesis of allergic asthma in patients and animals.

Methods

Studies were conducted in asthmatic patients and Chop−/− mice to dissect the role of Chop and ER stress in asthma pathogenesis. An ovalbumin (OVA)–induced allergic airway inflammation model was used to address the effect of Chop deficiency on asthma development. Next, the effect of Chop deficiency on macrophage polarization and related signaling pathways was investigated to demonstrate the underlying mechanisms.

Results

Asthmatic patients and mice after OVA induction exhibited aberrant Chop expression along with ER stress. Specifically, Chop was noted to be specifically overexpressed in macrophages, and mice deficient in Chop were protected from OVA-induced allergic airway inflammation, as manifested by attenuated airway inflammation, remodeling, and hyperresponsiveness. Chop was found to exacerbate allergic airway inflammation by enhancing M2 programming in macrophages. Mechanistic studies characterized an IL-4/signal transducer and activator of transcription 6/transcription factor EC (Tfec)/IL-4 receptor α positive feedback regulatory loop, in which IL-4 induces Chop expression, which then promotes signal transducer and activator of transcription 6 signaling to transcribe Tfec expression. Finally, Tfec transcribes IL-4 receptor α expression to promote M2 programming in macrophages.

Conclusions

Chop and ER stress are implicated in asthma pathogenesis, which involves regulation of M2 programming in macrophages.

Section snippets

Methods

Further details can be found in the Methods section in this article's Online Repository at www.jacionline.org.

Asthmatic patients and mice exhibit aberrant Chop expression and ER stress

We first examined the expression of CHOP in induced sputum samples obtained from asthmatic patients. CHOP was expressed at low levels in sputum derived from control subjects, whereas higher levels of CHOP were detected in induced sputum samples originating from asthmatic patients (Fig 1, A). We also examined the expression of binding immunoglobulin protein (BIP), another marker of ER stress. Similar to CHOP, BIP was expressed at significantly higher levels in asthmatic patients compared with

Discussion

In the present study we demonstrated that asthmatic patients and mice with OVA-induced allergic airway inflammation exhibit aberrant CHOP expression along with ER stress. Interestingly, CHOP was overexpressed in macrophages in both asthmatic patients and mice with OVA-induced allergic airway inflammation. Accordingly, Chop deficiency provided protection for mice against airway inflammation, remodeling, and AHR after repeated OVA challenges. Specifically, the loss of Chop protected mice from

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    Disclosure of potential conflict of interest: All of the authors declare that their institutions received the National Natural Science Foundation of China (81130014, 81530024, 81428001, 81470226, and 81570024), the Program Project for Chronic Diseases from the Ministry of Science and Technology (2016YFC1305002), the Funding for Generation of Experimental Animals from the Hubei State Technology Department (2015BCE100), the Program for Changjiang Scholars and Innovative Research Team in University (IRT_14R20), and the Multi-interdisciplinary Creative Team for Diabetes Research (2017-4) from Tongji Medical College, Huazhong University of Science & Technology.

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