Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma

Abstract

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.

Keywords: eosinophil progenitors; eosinophilopoiesis; eosinophils; epithelial-derived cytokines; interleukin-5.

Figure 1

Transcription factors that instruct eosinophil differentiation. A number of transcription factors control eosinophil-lineage commitment and differentiation to mature eosinophils. A decline in FOG-1 and increased IRF8 up-regulates C/EBPα, with subsequent GATA-1/GATA-2 expression. Collective IRF8, PU.1, C/EBPα, and C/EBPε expression results in eosinophil-lineage commitment, followed by collaboration between C/EBPε, PU.1, GATA-1, and GATA-2 for progression to mature eosinophils. XBP1 and balanced ID1/ID2 expression allows for eosinophil granule protein synthesis and survival. Abbreviations: C/EBPα= CAAT/enhancer binding protein alpha; C/EBP = CAAT/enhancer binding protein epsilon; EoP = Eosinophil progenitor; FOG-1 = Friend of GATA-1; GATA-1 = Globin transcription binding factor-1; HPC = Hematopoietic progenitor cells; ID1 = Inhibitor of DNA-binding proteins 1; ID2 = Inhibitor of DNA-binding proteins 2; IL-5Rα = Interleukin-5 receptor alpha; IRF8 = Interferon regulatory factor 8.

Figure 2

Eosinophilopoietic processes in asthma-damaged airway epithelial cells release alarmins, which activate local ILC2s, resulting in release of type 2 cytokines, including IL-5, IL-4, and IL-13. Growth factors (IL-5/IL-3/GM-CSF) produced by local effector cells and airway epithelium, in combination with alarmins, induce in situ eosinophilopoiesis. The migration of HPCs, EoPs, and eosinophils is mediated by local and systemic chemo-attractants, including eotaxin, which is enhanced by local CysLTs, alarmin cytokines, and type 2 cytokines. Within the airways, eosinophils contribute to tissue damage and airway remodeling through the production of granule proteins. Numerous targets have been identified that may attenuate both eosinophil and EoP activity, including CCR3, IL-5, IL-4/IL-13, common beta chain, CysLT receptor, and alarmins. Abbreviations: ASM = Airway smooth muscle; AHR = Airway hyperresponsiveness; BC = Bronchoconstriction; CysLT = Cysteinyl leukotrienes; Eo = Eosinophil; EoP = Eosinophil Progenitor Cell; HPCs = Hematopoietic progenitor cells; ILC2 = Group 2 innate lymphoid cells.