Human Bronchial Epithelial Cell–derived Factors from Severe Asthmatic Subjects Stimulate Eosinophil Differentiation

Salter, Brittany; Smith, Steven G; Mukherjee, Manali; Plante, Sophie; Krisna, Sai Sakktee; Nusca, Graeme; Oliveria, John Paul; Irshad, Anam; Gauvreau, Gail M.; Chakir, Jamila; Nair, Parameswaran; Sehmi, Roma

doi:10.1165/rcmb.2016-0262oc

Cited by 30 publications

(19 citation statements)

References 35 publications

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“…S3), was detectable promptly after compression and was accompanied by a marked induction of epithelial alarmins, including IL-33 and TSLP. While a supportive activity of these factors has been documented for a variety of accessory immune cells 43,44 , IL-33 and TSLP are central for example to the initiation and enhancement of type 2 response typically seen in asthmatic inflammation [45][46][47][48] . Following compression (3 hr), an increased release of these factors from airway epithelial cells could activate type 2 innate lymphoid cells (ILC2) and augment type 2 inflammation in the lung 43,48,49 .…”

Section: Discussionmentioning

confidence: 99%

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Kılıç

Ameli

Park

et al. 2020

Sci Rep

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Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufficient to induce inflammatory, late repair, and fibrotic pathways. Remarkably, this molecular profile of non-asthmatic cells after compression recapitulated the profile of asthmatic cells before compression. Together, these results show that even in the absence of any inflammatory stimulus, mechanical compression alone is sufficient to induce an asthma-like molecular signature. Bronchial epithelial cells (BECs) form a physical barrier that protects pulmonary airways from inhaled irritants and invading pathogens 1,2. Moreover, environmental stimuli such as allergens, pollutants and viruses can induce constriction of the airways 3 and thereby expose the bronchial epithelium to compressive mechanical stress. In BECs, this compressive stress induces structural, biophysical, as well as molecular changes 4,5 , that interact with nearby mesenchyme 6 to cause epithelial layer unjamming 1 , shedding of soluble factors, production of matrix proteins, and activation matrix modifying enzymes, which then act to coordinate inflammatory and remodeling processes 4,7-10. Growing evidence supports the notion that mechanical stress in the airway induces not only developmental, homeostatic and reparative responses in the healthy lung but also pathophysiologic processes in the asthmatic lung 2,11-13. For example, mechanical stimuli induce early inflammatory and remodeling factors 6,7,14,15 , microRNAs (miRs) 16,17 , and cell proliferation 18. Using protein-protein interaction networks, here we compare responses to compressive stress in human BECs (HBECs) obtained from non-asthmatic versus asthmatic donors. Our hypothesis was, that using a systems biology approach to examine the effect of mechanical forces acting on structural cells in the airway, will elucidate the complex transcriptional programs that contribute to disease development and pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Kılıç

Ameli

Park

et al. 2020

Sci Rep

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“…Epithelial cell–derived cytokines have effects on numerous proinflammatory cells and are reviewed elsewhere . A primary target of epithelial cell–derived stress cytokines, TSLP, IL‐33, and IL‐25 are a novel group of cells termed group 2 innate lymphoid cells (ILC2s).…”

Section: Introductionmentioning

confidence: 99%

The role of type 2 innate lymphoid cells in eosinophilic asthma

Salter

Sehmi

2019

Journal of Leukocyte Biology

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Eosinophilic asthma has conventionally been proposed to be a T helper 2 driven disease but emerging evidence supports a central role of type 2 innate lymphoid cells (ILC2s). These are non-T, non-B cells that lack antigen specificity and produce more IL-5 and IL-13 than CD4 + T lymphocytes, on a cell per cell basis, in vitro. Although it is clear that ILC2s and CD4 + T cells work in concert with each other to drive type 2 immune responses, kinetic studies in allergic asthma suggest that ILC2s may act locally within the airways to "initiate" eosinophilic responses, whereas CD4 + T cells act locally and systemically to "perpetuate" eosinophilic inflammatory responses. Importantly, ILC2s are increased within the airways of severe asthmatics, with the greatest number of IL-5 + IL-13 + ILC2s being detected in sputum from severe asthmatics with uncontrolled eosinophilia despite high-dose steroid therapy. Although the precise relationship between ILC2s and steroid sensitivity in asthma remains unclear, controlling the activation of ILC2s within the airways may provide an effective therapeutic target for eosinophilic inflammation in airways diseases. K E Y W O R D Seosinophilic asthma, eosinophilopoiesis, innate lymphoid cells NMU, neuromedin U; NMUR, neuromedin U receptor; PC 20 , concentration required to achieve a 20% decrease in FEV 1 ; PLZF, pro-myelocytic leukemia zinc finger; TOX, thymocyte selection associated HMB boxprotein; TSLP, thymic stromal lymphopoietin; TSLPR, thymic stromal lymphopoietin receptor. this review, we will discuss the role of innate lymphoid cells (ILCs) in eosinophilic asthma and the potential targets that drive persistent airway eosinophilia.

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“…The eosinophilopoietic potential of TSLP was first demonstrated in humans using cord-derived CD34 + cells, where TSLP stimulated the growth of Eo/B-CFU in 14-day methylcellulose cultures, which was enhanced in the presence of IL-3 and TNFα [ 38 ]. Similarly, the outgrowth of Eo/B-CFU in cultures of progenitor cells with bronchial epithelial cell-derived supernatants from severe asthmatics was reported and shown to be attenuated by TSLP blockade [ 39 ]. Furthermore, recombinant human TSLP, at picogram levels, stimulated the formation of Eo/B-CFU, with additive effects when combined with IL-5, in vitro.…”

Section: Regulation Of Eosinophilopoiesismentioning

confidence: 99%

“…Furthermore, recombinant human TSLP, at picogram levels, stimulated the formation of Eo/B-CFU, with additive effects when combined with IL-5, in vitro. At the mRNA level, a synergistic increase in GATA-2 and C/EBPα in CD34 + cells were detected in the presence of TSLP and IL-5, indicating that TSLP can act either alone or in concert with traditional eosinophilopoietins to promote eosinophilopoiesis [ 39 ].…”

Section: Regulation Of Eosinophilopoiesismentioning

confidence: 99%

Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma

Salter

Sehmi

2021

Cells

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Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.

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Human Bronchial Epithelial Cell–derived Factors from Severe Asthmatic Subjects Stimulate Eosinophil Differentiation

Cited by 30 publications

References 35 publications

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

The role of type 2 innate lymphoid cells in eosinophilic asthma

Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma

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