Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells.

Abdulrahman Alzahrani,Fahad Alhadian,Omar Tliba,Yassine Amrani,Katy M Roach,Jameel Hakeem,Aamir Hussain,Peter Bradding,Michael Biddle,Latifa Khalfaoui

doi:10.3389/falgy.2021.785100

Abdulrahman Alzahrani, Fahad Alhadian + Show 8 more

Open Access

https://doi.org/10.3389/falgy.2021.785100

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Abstract

The mechanisms underlying corticosteroid insensitivity in severe asthma have not been elucidated although some indirect clinical evidence points toward a role of mast cells. Here, we tested the hypothesis that mast cells can drive corticosteroid insensitivity in airway smooth muscle cells, a key player in asthma pathogenesis. Conditioned media from resting or FcεR1-activated human lung mast cells were incubated with serum-deprived ASM cells (1:4 dilution, 24 h) to determine their impact on the anti-inflammatory action of fluticasone on ASM cell chemokine expression induced by TNFα (10 ng/ml). Conditioned media from FcεR1-activated mast cells (but not that from non-activated mast cells or control media) significantly reduced the ability of 100 nM fluticasone to suppress ASM TNFα-dependent CCL5 and CXCL10 production at both mRNA and protein levels. In contrast, fluticasone inhibition of CXCL-8 production by TNFα was still preserved in the presence of activated mast cell conditioned media. Transcriptomic analysis validated by individual qPCR assays revealed that activated mast cell conditioned media dramatically reduced the number of anti-inflammatory genes induced by fluticasone in ASM cells. Our study demonstrates for the first time that conditioned media from FcεR1-activated mast cells blunt the anti-inflammatory action of corticosteroids in ASM cells by altering their transactivation properties. Because infiltration of mast cells within the ASM bundles is a defining feature of asthma, mast cell-derived mediators may contribute to the glucocorticoid insensitivity present in severe asthma.

Highlights

Both preclinical and clinical studies indicate a central role for mast cells in the pathogenesis of asthma, through their unique ability to produce an array of mediators capable of regulating key features of both the innate and adaptive immunity in the lungs [1]
Our present study demonstrates that activated mast cells can blunt the anti-inflammatory action of GC in human airway smooth muscle (ASM) cells, a key dysfunctional component of the airway wall in asthma
Our conditioned media approach revealed that mediators released from FCεR1-activated mast cells can alter the antiinflammatory action of GC, as no effect was seen in ASM cells treated with culture media or conditioned media from resting mast cells

Summary

Introduction

Both preclinical and clinical studies indicate a central role for mast cells in the pathogenesis of asthma, through their unique ability to produce an array of mediators capable of regulating key features of both the innate and adaptive immunity in the lungs [1]. Other mast cell mediators contribute to key structural/clinical features of asthma such as mucus hypersecretion, epithelium permeability, airway hyperresponsiveness (AHR), bronchoconstriction and airway remodeling [1]. Multiple triggers contribute to mast cell activation in asthma including stimulation of the high affinity IgE receptor FcεRI by allergens, ligands of the Toll like receptors, and cytokines activating the alarmin receptors (TSLP, IL-33) [1]. These different triggers, likely acting in concert, lead to both the acute and chronic mast cell activation that is observed in severe asthma, an important feature that is present irrespective of the clinical phenotype [2]

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