Coden, Mackenzie E.

Abstract Type 2 immune cells and eosinophils are transiently present in lung tissue not only in pathology but also during normal postnatal development. However, the lung developmental processes underlying postnatal airway recruitment of eosinophils after birth remain unexplored. We determined that in mice, mature eosinophils are recruited to the lung during P3–14, which corresponds to the primary septation/alveolarization phase of lung development. Developmental eosinophils peaked during P10–14 and exhibited Siglec-Fmed/highCD11c−/low phenotypes, similar to allergic asthma models. By interrogating the lung transcriptome and proteome during peak eosinophil recruitment in postnatal development, we identified markers that functionally capture mesenchymal-epithelial interface establishment (Nes, Smo, Wnt5a, Nog) and provisional extracellular matrix (ECM) deposition (Tnc, Postn, Spon2, Thbs2) as key lung morphogenetic events associating with eosinophils. We identifiedTenascin-C (TNC) as one of the key ECM markers in the lung epithelial-mesenchymal interface at the RNA and protein levels, consistently associating with eosinophils in development and disease. By RNA-seq analysis, naïve murine eosinophils cultured with TNC-enriched ECM significantly induced expression of Siglec-F, CD11c, eosinophil peroxidase, and other markers typical for activated eosinophils in development and allergic inflammatory responses. TNC knockout mice had an altered eosinophil recruitment profile in development. Collectively, our results indicate that lung morphogenetic processes associated with heightened Type 2 immunity are not merely tissue “background” but specifically guide immune cells both in development and pathology.

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. Review on the two-way communication between tissue and eosinophils, discussing eosinophil heterogeneity in the framework of biological processes occurring in different tissue states.