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

Abstract

SummaryFrom 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.

All along the watchtower: group 2 innate lymphoid cells in allergic responses

“…ILC2s expand in the lung in the first two weeks of life, immediately followed by a modest contraction phase, reaching adult levels between 4–6 weeks after birth [58,59]. The early expansion of lung ILC2s has been reported to be partially driven by IL-33, which is induced in a subset of epithelial cells after birth, and is associated with the type 2-biased environment in the developing lung [58,60].…”

“…The early expansion of lung ILC2s has been reported to be partially driven by IL-33, which is induced in a subset of epithelial cells after birth, and is associated with the type 2-biased environment in the developing lung [58,60]. The immediate expression of IL-33 following birth was suggested to be induced by pressure changes associated with the “first breath”, demonstrated by induction of IL-33 in E19 lungs exposed to vacuum [58]. A recent study found that exposure of neonate and postnatal mice to hyperoxia increased TSLP and IL-33, ILC2 activation, airway hyper reactivity, mucus production and downstream type 2 airway inflammation[61].…”

Innate lymphoid cells and allergic disease

“…28–31 This accumulation of ILC2 coincides with a wave of IL-33 expression in the lungs, primarily from nonhematopoietic (CD45 − ) Epithelial cell adhesion molecule expressing (EpCam + ) lung epithelial cells. 29 Conceptually, this IL-33 expression and ILC2 accumulation occurs during the alveolarization period of murine lung development with expansion and maturation of type II pneumocytes. Mice lacking IL-33 signaling had reduced numbers of ILC2 in the lungs at post-natal days 7, 10, and 14 consistent with a critical role for IL-33 in establishing the ILC2 compartment within the lungs.…”

“…Mice lacking IL-33 signaling had reduced numbers of ILC2 in the lungs at post-natal days 7, 10, and 14 consistent with a critical role for IL-33 in establishing the ILC2 compartment within the lungs. 28,29,31 In the lungs during the post-natal period, ILC2 are the major source of type 2 cytokines, and the recruitment of type 2-associated effector cells such as eosinophils and anti-inflammatory M2 macrophages critically depends upon ILC2. 29,31 Collectively, these changes promote type 2 immune skewing in the post-natal period that can be exacerbated with exposure to allergen and persist into adulthood.…”

“…28,29,31 In the lungs during the post-natal period, ILC2 are the major source of type 2 cytokines, and the recruitment of type 2-associated effector cells such as eosinophils and anti-inflammatory M2 macrophages critically depends upon ILC2. 29,31 Collectively, these changes promote type 2 immune skewing in the post-natal period that can be exacerbated with exposure to allergen and persist into adulthood. While ILC2 accumulation has been well characterized in the lungs, substantially less is known about ILC2 accumulation in other tissues.…”