First-Breath-Induced Type 2 Pathways Shape the Lung Immune Environment

Summary

From birth onward, the lungs are exposed to the external environment and therefore harbor a complex immunological milieu to protect this organ from damage and infection. We investigated the homeostatic role of the epithelium-derived alarmin interleukin-33 (IL-33) in newborn mice and discovered the immediate upregulation of IL-33 from the first day of life, closely followed by a wave of IL-13-producing type 2 innate lymphoid cells (ILC2s), which coincided with the appearance of alveolar macrophages (AMs) and their early polarization to an IL-13-dependent anti-inflammatory M2 phenotype. ILC2s contributed to lung quiescence in homeostasis by polarizing tissue resident AMs and induced an M2 phenotype in transplanted macrophage progenitors. ILC2s continued to maintain the M2 AM phenotype during adult life at the cost of a delayed response to Streptococcus pneumoniae infection in mice. These data highlight the homeostatic role of ILC2s in setting the activation threshold in the lung and underline their implications in anti-bacterial defenses.

Graphical Abstract

Highlights

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  The first breath triggers IL-33 induction by AEC2 in lungs of newborn mice

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  IL-33 promotes the perinatal expansion and activation of ST2-expressing ILC2s

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  ILC2-derived IL-13 polarizes newborn’s AMs into an M2 phenotype

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  This homeostatic type 2 pathway delays antibacterial effector responses

Abstract

The postnatal lung immune environment is largely unexplored. Saluzzo et al. find that birth is associated with the induction of an IL-33/ILC2/IL-13-driven immune response in mice. This type 2 response is preserved throughout life and maintains alveolar macrophages in an M2 phenotype at the expense of a delayed response to bacterial infections.