The Cogence Clinical Pearls Series

Th17-Mediated Asthma

Cogence Clinical Pearl

What the research says…

The first paper, from Current Opinions in Immunology, emphasizes the importance of Th17 cell mediated neutrophil influx in moderate and severe asthma. The second paper, from Journal of Inflammation (London), describes an underlying mechanism by which the neutrophil-dominant asthma is driven.

Application…

Neutrophil influx into tissue is driven strongly by Th17 cytokines IL-17a and f, IL-21, and IL-22. The second paper identifies HIF-1α as a driver of this mechanism in neutrophil-dominant asthma. HIF-1α is hypoxia-inducible factor 1 alpha, which is upregulated by low tissue oxygen and can be inhibited by berberine. This suggests two useful clinical approaches. First, it becomes important to inventory factors related to hypoxia, including anemias of any sort, circulatory issues, and respiratory issues. The asthma itself, of course, presents a significant respiratory issue that can drive HIF-1α levels up, so that presents a concern about loop reinforcement. Second, berberine is an inhibitor of HIF-1α, so it may be appropriate to use berberine in these cases, in addition to other STAT3/Th17 inhibitors like curcumin, resveratrol, vitamin A, sulforaphanes, etc.

Research…

Th17-mediated inflammation in asthma.
Newcomb DC, Peebles RS Jr. Curr Opin Immunol. 2013 Dec;25(6):755-60.

Abstract
Asthma is a heterogeneous disease with many different phenotypes. Moderate and severe asthma phenotypes have been associated with increased neutrophils and increased Th17 cytokines, IL-17A, IL-17F, and IL-22, in the bronchoalveolar lavage fluid of patients. Th17 cytokines recruit neutrophils to the airway by increasing secretion of epithelial-derived neutrophilic chemokines. In addition, Th17 cytokines also induce mucous cell metaplasia and have pleotropic effects on airway smooth muscle resulting in airway narrowing. The role of Th17 cytokines in regulating Th2 cytokine expression and allergic airway inflammation remains unclear with conflicting reports. However, the role of Th17 cells in asthma will be answered in ongoing clinical trials with therapeutics targeting IL-17A and IL-17 receptor signaling.

MBD2 regulates differentiation and function of Th17 cells in neutrophils- dominant asthma via HIF-1α.

Xu L, Sun WJ, Xiang XD, et al. J Inflamm (Lond). 2018 Aug 20;15:15.

Abstract

Background: T helper 17 (Th17) cells have proven to be crucial in the pathogenesis of neutrophils-dominant asthma. Hypoxia inducible factor-1α (HIF-1α) is involved in allergic responses in asthma. Our previous studies indicated that Methtyl-CpG binding domain protein 2 (MBD2) expression was increased in asthma patients. The aim of the present study is to understand how MBD2 interacts with HIF-1α to regulate Th17 cell differentiation and IL-17 expression in neutrophils-dominant asthma.

Methods: A neutrophils-dominant asthma mouse model was established using female C57BL/6 mice to investigate Th17 cell differentiation and MBD2 and HIF-1α expression regulation using flow cytometry, western blot or qRT-PCR. MBD2 and HIF-1α genes were silenced or overexpressed through lentiviral transduction to explore the roles of MBD2 in Th17 cell differentiation and IL-17 release in neutrophils-dominant asthma.

Results: A neutrophilic inflammatory asthma phenotype model was established successfully. This was characterized by airway hyperresponsiveness (AHR), increased BALF neutrophil granulocytes, activated Th17 cell differentiation, and high IL-17 levels. MBD2 and HIF-1α expression were significantly increased in the lung and spleen cells of mice with neutrophils-dominant asthma. Through overexpression or silencing of MBD2 and HIF-1α genes, we have concluded that MBD2 and HIF-1α regulate Th17 cell differentiation and IL-17 secretion. Moreover, MBD2 was also found to regulate HIF-1α expression.

Conclusion: Our findings have uncovered new roles for MBD2 and HIF-1α, and provide novel insights into the epigenetic regulation of neutrophils-dominant asthma.