Abstract
Type 2 immune cells and eosinophils are transiently present in the lung tissue not only in pathology (allergic disease, parasite expulsion) but also during normal postnatal development. However, the lung developmental processes underlying airway recruitment of eosinophils after birth remain unexplored. We determined that in mice, mature eosinophils are transiently recruited to the lung during postnatal days 3–14, which specifically 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 the establishment of the mesenchymal-epithelial interface (Nes, Smo, Wnt5a, Nog) and the deposition of the provisional extracellular matrix (ECM) (Tnc, Postn, Spon2, Thbs2) as a key lung morphogenetic event associating with eosinophils. Tenascin-C (TNC) was identified as one of the key ECM markers in the lung epithelial-mesenchymal interface both at the RNA and protein levels, consistently associating with eosinophils in development and disease in mice and humans. As determined by RNA-seq analysis, naïve murine eosinophils cultured with ECM enriched in TNC 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 a tissue “background” but specifically guide immune cells both in development and pathology.
Highlights
Type 2 immune cells and eosinophils are transiently present in the lung tissue in pathology and during normal postnatal development
We: (1) carefully dissected the recruitment kinetics of eosinophils relative to key developmental stages of the neonatal murine lung; (2) determined that peak eosinophil presence in the developing lung corresponds to the primary septation of the lung during the alveolarization phase of development, characterized by the formation of mature epithelium; (3) identified key morphogenetic signals, in particular the deposition of tenascin-C (TNC), that align with timing of lung eosinophil recruitment; (4) found that extracellular matrix enriched with TNC is sufficient to induce eosinophil activation consistent with the phenotype induced by development or lung allergic inflammation
We show that: (1) eosinophil participation in normal postnatal lung morphogenesis is restricted to the bulk septation and alveolarization phases of development; (2) eosinophils associate with the deposition of the provisional extracellular matrix (ECM) and mesenchymal developmental activity; (3) the composition of the ECM matters, as it drives differential eosinophil responses; (4) the provisional ECM is sufficient to promote a phenotype consistent with eosinophil tissue activation in allergic inflammation
Summary
Type 2 immune cells and eosinophils are transiently present in the lung tissue in pathology (allergic disease, parasite expulsion) and during normal postnatal development. ILC2s are thought to drive Type 2 immunity in the neonatal lung, which associates with Type 2 cytokine production (IL-5 and IL-13), M2 macrophage polarization, and temporal increases in eosinophil numbers[15,16,17] How these transient events relate to normal lung developmental programs is currently unknown. We: (1) carefully dissected the recruitment kinetics of eosinophils relative to key developmental stages of the neonatal murine lung; (2) determined that peak eosinophil presence in the developing lung (postnatal days 10–14) corresponds to the primary septation of the lung during the alveolarization phase of development, characterized by the formation of mature epithelium; (3) identified key morphogenetic signals, in particular the deposition of tenascin-C (TNC), that align with timing of lung eosinophil recruitment; (4) found that extracellular matrix enriched with TNC is sufficient to induce eosinophil activation consistent with the phenotype induced by development or lung allergic inflammation. Eosinophil recruitment to the lung during postnatal development (modeling) and allergic disease (re-modeling) may represent an inherently homeostatic response of the innate immune system driven by morphogenesis of the airway epithelium
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