Through its role in metabolizing the amino acid L-arginine, ARG1 contributes to the generation of metabolites that are essential for collagen synthesis and cell proliferation. Metabolism of L-arginine mainly occurs in the liver, but expression of ARG1 is a key marker of alternatively activated macrophages, which promote tissue fibrosis by secreting this enzyme. However, global inhibition of ARG1 has a more profound effect in limiting fibrotic airway disease than does macrophage-restricted targeting of ARG1, suggesting that other ARG1-expressing cells contribute to airway disease. Using Arg1 reporter mice, the authors showed that ARG1 is a marker of lineage-committed ILC2 precursors in the bone marrow and is constitutively expressed by ILC2s from diverse tissue sites. As ILC2s are the predominant ILC subset found in the mouse lungs, the authors examined whether these cells represent a major source of ARG1 in the lungs. Indeed, under homeostatic conditions they found that ILC2s — as opposed to alveolar macrophages or other immune cells — are the dominant source of ARG1.
In mice with papain-induced airway inflammation, ILC2s were also a major source of ARG1, and total ARG1+ ILC2 numbers increased in the inflamed lungs. Furthermore, examination of lung tissue extracts from patients with inflammatory airway diseases showed that ILC2s express ARG1 to a similar extent as myeloid cells in the inflamed human lungs. To assess whether ILC2-derived ARG1 contributes to airway inflammation, the authors generated mice with an ILC-specific deletion of Arg1 (Arg1ΔILC mice). Compared with controls, Arg1ΔILC mice had similar frequencies of ILC2s in the resting lungs. However, following papain challenge, ILC2 responses were markedly diminished in Arg1ΔILC mice, and these animals showed reduced airway inflammation. Similarly, in models of chronic lung inflammation, ILC2 responses and levels of airway inflammation were suppressed in Arg1ΔILC mice. By contrast, Arg1ΔLyz2 mice (in which Arg1 is deleted in macrophages and neutrophils) developed similar levels of lung inflammation as controls in response to papain challenge. This suggests that ARG1 expression in ILC2s, as opposed to in myeloid cells, is important for the development of acute airway inflammation.
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