Coexpression of IL-5 and Eotaxin-2 in Mice Creates an Eosinophil-Dependent Model of Respiratory Inflammation with Characteristics of Severe Asthma

Abstract

Mouse models of allergen provocation and/or transgenic gene expression have provided significant insights regarding the cellular, molecular, and immune responses linked to the pathologies occurring as a result of allergic respiratory inflammation. Nonetheless, the inability to replicate the eosinophil activities occurring in patients with asthma has limited their usefulness to understand the larger role(s) of eosinophils in disease pathologies. These limitations have led us to develop an allergen-naive double transgenic mouse model that expresses IL-5 systemically from mature T cells and eotaxin-2 locally from lung epithelial cells. We show that these mice develop several pulmonary pathologies representative of severe asthma, including structural remodeling events such as epithelial desquamation and mucus hypersecretion leading to airway obstruction, subepithelial fibrosis, airway smooth muscle hyperplasia, and pathophysiological changes exemplified by exacerbated methacholine-induced airway hyperresponsiveness. More importantly, and similar to human patients, the pulmonary pathologies observed are accompanied by extensive eosinophil degranulation. Genetic ablation of all eosinophils from this double transgenic model abolished the induced pulmonary pathologies, demonstrating that these pathologies are a consequence of one or more eosinophil effector functions.

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

“…32,33,54 -58 Since the introduction of the Th1/Th2 paradigm, IL-4 has been tightly associated with Th2 responses 59 -61 ; there is clear evidence that IL-4 is indispensable for Th2 maintenance. 62 For Th2 initiation, current studies point to nonhematopoietic cells that appear to be able to support innate immune cells by secretion of chemokines 63 and novel cytokines, such as IL-33, 33 IL-25, 32,58 and thymic stromal lymphopoietin (TSLP). 64 In pulmonary cryptococcosis, airway epithelial cells and eosinophils would be candidates for cross talk between resident tissue cells and leukocytes.…”

Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice

“…As described in earlier studies by Ochkur et al, 33 after flow cytometric sorting, eosinophils were fixed in Trump's fixative (1% glutaraldehyde, 4% formaldehyde, 0.1 M phosphate buffer; pH 7.2) prior to preparation for electron microscopy and photographic evaluations.…”

Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

“…To establish whether eosinophils were necessary for the protective effects of IL-5 in sepsis, NJ.1638 mice were crossed with PHIL 1/2 mice, which express a diphtheria toxin transgene under control of the eosinophil peroxidase promoter (28,29). NJ.1638/PHIL mice constitutively overexpress IL-5, but have a congenital deficiency in eosinophils thereby enabling accurate assessment of the independent effects of IL-5 in sepsis (28,29,35). Unexpectedly, NJ.1638/PHIL mice had improved survival over littermate controls in CLP ( Figure 3A), suggesting an important role in vivo for IL-5 in the absence of eosinophils.…”