Re-defining the unique roles for eosinophils in allergic respiratory inflammation

Abstract

The role of eosinophils in the progression and resolution of allergic respiratory inflammation is poorly defined despite the commonality of their presence and in some cases their use as a biomarker for disease severity and/or symptom control. However, this ambiguity belies the wealth of insights that have recently been gained through the use of eosinophil-deficient/attenuated strains of mice that have demonstrated novel immunoregulatory and remodelling/repair functions for these cells in the lung following allergen provocation. Specifically, studies of eosinophil-deficient mice suggest that eosinophils contribute to events occurring in the lungs following allergen provocation at several key moments: (i) the initiating phase of events leading to Th2-polarized pulmonary inflammation, (ii) the suppression Th1/Th17 pathways in lung-draining lymph nodes, (iii) the recruitment of effector Th2 T cells to the lung, and finally, (iv) mechanisms of inflammatory resolution that re-establish pulmonary homoeostasis. These suggested functions have recently been confirmed and expanded upon using allergen provocation of an inducible eosinophil-deficient strain of mice (iPHIL) that demonstrated an eosinophil-dependent mechanism(s) leading to Th2 dominated immune responses in the presence of eosinophils in contrast to neutrophilic as well as mixed Th1/Th17/Th2 variant phenotypes in the absence of eosinophils. These findings highlighted that eosinophils are not exclusively downstream mediators controlled by T cells, dendritic cells (DC) and/or innate lymphocytic cells (ILC2). Instead, eosinophils appear to be more aptly described as significant contributors in complex interrelated pathways that lead to pulmonary inflammation and subsequently promote resolution and the re-establishment of homoeostatic baseline. In this review, we summarize and put into the context the evolving hypotheses that are now expanding our understanding of the roles eosinophils likely have in the lung following allergen provocation.

Figure 1. Eosinophil Functions in Allergic Respiratory Inflammation

Through the use of eosinophil-deficient/attenuated strains of mice and adoptive transfer techniques in models of allergic respiratory inflammation various effector functions of eosinophils have been identified. These effector functions include role(s) in (1) Initiation, (2) Polarization/Proliferation, (3) Recruitment of Th2 cells/Th2 propagation, and (4) Resolution of the inflammatory events. (1) Initiation. Stromal cells and resident leukocytes respond to airway allergens by producing cytokines, chemokines, and other mediators that aid in the recruitment and activation of eosinophils to the lung. Eotaxin-1 (CCL11) and eotaxin-2(CCL24) by epithelial cells, macrophage, and endothelial cells recruit eosinophils to the lung from the periphery. L-33 and GM-CSF aid in activation and survival of eosinophils once in the lung. Eosinophils enhance their survival via autocrine and paracrine release of mediators (e.g., IL-5 and GM-CSF). Eosinophils enhance the activities of other cells through release of mediators (e.g., cytokine, reactive oxygen species, leukotrienes, lipids, and granule proteins). (2) Polarization/Proliferation. Once eosinophils are primed in the lung they migrate to the lung draining lymph node (LDLN) to aid in the secondary immune response. In particular, eosinophils are necessary for antigen-specific T cell proliferation in an MHC II-independent manner in the LDLN through inducing accumulation of DCs. Eosinophils suppress Th1/Th17 polarization and enhance Th2 polarization through release of mediators that are undefined, but may include IDO, TGF-β, and IL-10. (3) Recruitment of Th2 cells/Th2 Propagation. Eosinophils are necessary to induce recruitment of effector Th2 T cells through the production of TARC and MDC. Eosinophils enhance accumulation and activation of DCs. Eosinophils aid in the propagation of inflammatory responses through production of IL-4 and IL-13, as well as other mediators (e.g., cytokine, reactive oxygen species, leukotrienes, lipids, and granule proteins). (4) Resolution. Eosinophils may contribute to the resolution process by polarization of macrophage to M2 (via IL-4/13) and through release of protectins and resolvins (12/15-lipoxygenase products). Failure to polarize toward Th2 and to resolve inflammation may predispose the inflammation toward a neutrophilic/Th1/Th17 phenotype.