Inhibition of miR-99a-5p prevents allergen-driven airway exacerbations without compromising type-2 memory responses in the intestine following helminth infection

Lewis J Entwistle ,Sean Flanagan,Riccardo Guidi,Helena Aegerter,Angela Martzall,Dennis Wilson,Shannon Hambro,Probir Chakravaty,Yi Cao,Alison Huynh,Jessica Mills,Laurie Leong,Christine L Clarke ,Cary D Austin ,Nikolay P Nikolov ,Víctor Núñez ,Abdul Karim Sesay ,Eleni Amaniti,Stephanie Czieso,Mark S Wilson

doi:10.1038/s41385-021-00401-x

Lewis J Entwistle , Sean Flanagan + Show 18 more

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https://doi.org/10.1038/s41385-021-00401-x

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Journal: Mucosal Immunology	Publication Date: Apr 12, 2021
Citations: 6	License type: open-access

Affiliation: The Francis Crick Institute

Abstract

Acute exacerbations (AE) of asthma, remain one of the biggest concerns for patients living with asthma. As such, identifying the causes, the molecular mechanisms involved and new therapeutic interventions to prevent AE is a high priority. Immunity to intestinal helminths involves the reactivation of type-2 immune responses leading to smooth muscle contraction and mucus hypersecretion–physiological processes very similar to acute exacerbations in the airways following allergen exposure. In this study, we employed a murine model of intestinal helminth infection, using Heligmosomoides polygyrus, to identify miRNAs during active expulsion, as a system for the identification of miRNAs that may contribute to AE in the airways. Concomitant with type-2 immunity and expulsion of H. polygyrus, we identified miR-99a-5p, miR-148a-3p and miR-155-5p that were differentially regulated. Systemic inhibition of these miRNAs, alone or in combination, had minimal impact on expulsion of H. polygyrus, but inhibition of miR-99a-5p or miR-155-5p significantly reduced house dust mite (HDM)-driven acute inflammation, modelling human acute exacerbations. Immunological, pathological and transcriptional analysis identified that miR-155-5p or miR-99a-5p contribute significantly to HDM-driven AE and that transient inhibition of these miRNAs may provide relief from allergen-driven AE, without compromising anti-helminth immunity in the gut.

Highlights

Allergic diseases, including rhinitis, eczema and asthma remain a growing global public health concern
Using a series of in silico filtering methods and analyses, we focused on 3 miRNAs, miR-155-5p, miR-99a-5p and miR-148a-3p, that were significantly elevated during active expulsion- hypothesising that miRNAs at these time points may have a greater likelihood of contributing to the acute type-2 immune response and/or tissue responses
Intestinal miRNAs are differentially expressed during acute H. polygyrus infection, in mice resistant to secondary H. polygyrus infection and during active expulsion To characterise the intestinal miRNAome during anti-helminth immunity, we infected C57BL/6 mice with 200 L3 larvae of the natural mouse intestinal helminth Heligmosomoides polygyrus.[11]

Summary

Introduction

Allergic diseases, including rhinitis, eczema and asthma remain a growing global public health concern. Our understanding of disease pathogenesis, and development of therapeutic interventions, has largely focused on targeting type-2 immune responses[1,2,3,4] and in particular at the cytokine, immunoglobulin and cellular level. There remains a need for novel interventions, modalities and targets to treat patients that are not currently met with standard of care (SOC) that do not benefit from the current therapeutics. The precise aetiology of AE is broad, including microbial, occupational and environmental irritants, allergen-driven AE are relatively well described, can be modelled accurately in mice and can be translated into clinical settings in allergen challenge studies.[5]

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