Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone‐dependent severe asthma

Sehmi, Roma; Smith, Steven G; Kjarsgaard, Melanie; Radford, Katherine; Boulet, Louis‐Philippe; Lemière, Catherine; Prazma, Charlene M.; Ortega, Héctor; Martin, James G.; Nair, Parameswaran

doi:10.1111/cea.12695

Cited by 103 publications

(104 citation statements)

References 41 publications

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“…While anti-IL-5 therapies reduce the occurrences of asthma exacerbations in severe eosinophilic asthma[3, 4], airway eosinophil precursors remain mostly unaffected by these therapies [54-56]. We and others previously showed that IL-5 receptor α is downregulated on IL-5-activated blood eosinophils as well as airway eosinophils obtained after airway allergen challenge [11-13].…”

Section: Discussionmentioning

confidence: 99%

IL‐3 up‐regulates and activates human eosinophil CD32 and αMβ2 integrin causing degranulation

Esnault

Johansson

Kelly

et al. 2017

Clin Experimental Allergy

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Background Eosinophils contribute to the pathogenesis of multiple diseases, including asthma. Treatment with antibodies targeting IL-5 or IL-5 receptor α reduces the frequency of asthma exacerbations. Eosinophil receptors for IL-5 share a common ß-chain with IL-3 and GM-CSF receptors. We recently reported that IL-3 is more potent than IL-5 or GM-CSF in maintaining the ERK/p90S6K/RPS6 ribosome-directed signaling pathway, leading to increased protein translation. Objective We aimed to determine disease-relevant consequences of prolonged eosinophil stimulation with IL-3. Methods Human blood eosinophils were used to establish the impact of activation with IL-3 on IgG-driven eosinophil degranulation, which was then compared to IgG-mediated degranulation of freshly isolated (unstimulated) airway eosinophils activated in vivo by segmental allergen challenge. Results When compared to IL-5, continuing exposure to IL-3 further induced degranulation of eosinophils on aggregated IgG via increased production and activation of both CD32 (low affinity IgG receptor) and αMß2 integrin. In addition, unlike IL-5 or GM-CSF, IL-3 induced expression of CD32B/C (FCGRIIB/C) subtype proteins, without changing CD32A (FCGRIIA) protein and CD32B/C mRNA expression levels. Importantly, these in vitro IL-3-induced modifications were recapitulated in vivo on airway eosinophils. Conclusions We observed for the first time upregulation of CD32B/C on eosinophils, and identified IL-3 as a potent inducer of CD32- and αMß2-mediated eosinophil degranulation.

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Section: Discussionmentioning

confidence: 99%

IL‐3 up‐regulates and activates human eosinophil CD32 and αMβ2 integrin causing degranulation

Esnault

Johansson

Kelly

et al. 2017

Clin Experimental Allergy

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“…Eosinophil-lineage committed cells have also been identified in lung tissue in a mouse model of allergic airway inflammation (26). More recently, eosinophil progenitors isolated from the blood of patients with severe eosinophilic asthma have been shown to have an exaggerated clonogenic response to IL-5 in vitro , compared to eosinophil precursors from mild asthmatics, suggesting that in situ eosinophilopoiesis may have a clinically relevant role in severe eosinophilic asthma (27). …”

Section: Eosinophil Differentiation Maturation Migration Activatiomentioning

confidence: 99%

The Biology of Eosinophils and Their Role in Asthma

2017

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This review will describe the structure and function of the eosinophil. The roles of several relevant cell surface molecules and receptors will be discussed. We will also explore the systemic and local processes triggering eosinophil differentiation, maturation, and migration to the lungs in asthma, as well as the cytokine-mediated pathways that result in eosinophil activation and degranulation, i.e., the release of multiple pro-inflammatory substances from eosinophil-specific granules, including cationic proteins, cytokines, chemokines growth factors, and enzymes. We will discuss the current understanding of the roles that eosinophils play in key asthma processes such as airway hyperresponsiveness, mucus hypersecretion, and airway remodeling, in addition to the evidence relating to eosinophil–pathogen interactions within the lungs.

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“…Eosinophil progenitors are increased in the blood and sputum of asthmatic patients (65, 66), but their role in disease not fully understood. Intravenous IL-5 increased not only circulating eosinophil progenitors but also CCR3 expression on CD34 + progenitors (67).…”

Section: The Effects Of Il-33 On Mature and Developing Eosinophilsmentioning

confidence: 99%

Understanding Interleukin 33 and Its Roles in Eosinophil Development

Johnston

Bryce

2017

Front. Med.

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Over the last decade, significant interest in the contribution of three “epithelial-derived cytokines,” such as thymic stromal lymphopoietin, interleukin 25, and interleukin 33 (IL-33), has developed. These cytokines have been strongly linked to the early events that occur during allergen exposures and how they contribute to the subsequent type 2 immune response. Of these three cytokines, IL-33 has proven particularly interesting because of the strong associations found between both it and its receptor, ST2, in several genome-wide association studies of allergic diseases. Further work has demonstrated clear mechanisms through which this cytokine might orchestrate allergic inflammation, including activation of several key effector cells that possess high ST2 levels, including mast cells, basophils, innate lymphoid cells, and eosinophils. Despite this, controversies surrounding IL-33 seem to suggest the biology of this cytokine might not be as simple as current dogmas suggest including: the relevant cellular sources of IL-33, with significant evidence for inducible expression in some hematopoietic cells; the mechanistic contributions of nuclear localization vs secretion; secretion and processing mechanisms; and the biological consequences of IL-33 exposure on different cell types. In this review, we will address the evidence for IL-33 and ST2 regulation over eosinophils and how this may contribute to allergic diseases. In particular, we focus on the accumulating evidence for a role of IL-33 in regulating hematopoiesis and how this relates to eosinophils as well as how this may provide new concepts for how the progression of allergy is regulated.

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Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone‐dependent severe asthma

Cited by 103 publications

References 41 publications

IL‐3 up‐regulates and activates human eosinophil CD32 and αMβ2 integrin causing degranulation

IL‐3 up‐regulates and activates human eosinophil CD32 and αMβ2 integrin causing degranulation

The Biology of Eosinophils and Their Role in Asthma

Understanding Interleukin 33 and Its Roles in Eosinophil Development

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