Shaping eosinophil identity in the tissue contexts of development, homeostasis, and disease

Abstract

Eosinophils play homeostatic roles in different tissues and are found in several organs at a homeostatic baseline, though their tissue numbers increase significantly in development and disease. The morphological, phenotypical, and functional plasticity of recruited eosinophils are influenced by the dynamic tissue microenvironment changes between homeostatic, morphogenetic, and disease states. Activity of the epithelial-mesenchymal interface, extracellular matrix, hormonal inputs, metabolic state of the environment, as well as epithelial and mesenchymal-derived innate cytokines and growth factors all have the potential to regulate the attraction, retention, in situ hematopoiesis, phenotype, and function of eosinophils. This review examines the reciprocal relationship between eosinophils and such tissue factors, specifically addressing: (1) tissue microenvironments associated with the presence and activity of eosinophils; (2) non-immune tissue ligands regulatory for eosinophil accumulation, hematopoiesis, phenotype, and function (with an emphasis on the extracellular matrix and epithelial-mesenchymal interface); (3) the contribution of eosinophils to regulating tissue biology; (4) eosinophil phenotypic heterogeneity in different tissue microenvironments, classifying eosinophils as progenitors, steady state eosinophils, and Type 1 and 2 activated phenotypes. An appreciation of eosinophil regulation by non-immune tissue factors is necessary for completing the picture of eosinophil immune activation and understanding the functional contribution of these cells to development, homeostasis, and disease.

Keywords: asthma; development; eosinophils; epithelium; extracellular matrix; homeostasis; in situ hematopoiesis; mesenchyme; metabolism; phenotype.

Figure 1

Eosinophils associate with transient epithelial differentiation (modeling) events in development and persistent (remodeling) loss of differentiation in allergic disease. The two processes are analogous. The only apparent difference between the normal and pathological states of tissue undergoing remodeling is in heterochrony: the timing of onset, offset, and persistence of these signals. In normal development and injury repair, homeostatic modeling programs are perfectly timed while in disease they are perpetuated, perhaps associated with a continuous attempt to return the tissue to its homeostatic state. Changes in eosinophil phenotype typically associate with morphogenetic changes in tissue environment.

Figure 2

Eosinophils are well equipped to interact with all components of their tissue microenvironment. Representative receptors are illustrated that correspond to the diverse tissue ligands and cellular processes encountered both by mature and immature eosinophils in the contexts of development, homeostasis, and disease.

Figure 3

Eosinophil in the context of its immediate non-immune tissue microenvironment. Eosinophils are both affected by and affect their tissue environments. Eosinophil-tissue interactions are governed both on the systemic level by changes in nutrient availability, hormones, lipids, and overall metabolism (purple) and by tissue-specific processes, such as activation of the epithelial-mesenchymal interface and ECM deposition (light blue). During such activation of tissue programs, eosinophils receive multiple tissue inputs such as alarmins, DAMPs, ECM molecules, lipids, hormones, and metabolites (dark blue arrows). They respond to these cues by releasing products (red arrows) in an effort to return the tissue to homeostatic conditions. Balanced communication of different tissue components and systemic factors (green arrows) is necessary to maintain peripheral tissue homeostasis.

Figure 4

Tissue-based classification of murine eosinophils. EoP: Eosinophil Progenitors - immature eosinophils or committed precursors undergoing in situ hematopoiesis. Steady State: true resident eosinophils in morphogenetically quiescent tissues, featuring non-segmented “donut-shape” nuclear morphology and eosin staining. Type 1: interstitial/stromal eosinophils found in transient morphogenetic contexts and during Type 1 immune activation, featuring segmented nuclear morphology but lacking vacuolarization. Type 2: eosinophils associated with the epithelium and Type 2 immune environment, characterized by highly segmented nuclei and the presence of vacuoles.