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Airway macrophage-intrinsic TGF-β1 regulates pulmonary immunity during early life allergen exposure.
journal contributionposted on 2021-05-11, 13:06 authored by William J Branchett, James Cook, Robert A Oliver, Nicoletta Bruno, Simone A Walker, Helen Stӧlting, Matthias Mack, Anne O'Garra, Sejal Saglani, Clare M Lloyd
BACKGROUND: Early life represents a major risk window for asthma development. However, the mechanisms controlling the threshold for establishment of allergic airway inflammation in early life are incompletely understood. Airway macrophages (AMs) regulate pulmonary allergic responses and undergo TGF-β-dependent postnatal development, but the role of AM maturation factors such as TGF-β in controlling the threshold for pathogenic immune responses to inhaled allergens remains unclear. OBJECTIVE: Test the hypothesis that AM-derived TGF-β1 regulates pathogenic immunity to inhaled allergen in early life. METHODS: Conditional knockout (Tgfb1ΔCD11c) mice, with TGF-β1 deficiency in AMs and other CD11c+ cells, were analysed throughout early life and following neonatal house dust mite (HDM) inhalation. The roles of specific chemokine receptors were determined using in vivo blocking antibodies. RESULTS: AM-intrinsic TGF-β1 was redundant for initial population of the neonatal lung with AMs, but AMs from Tgfb1ΔCD11c mice failed to adopt a mature homeostatic AM phenotype in the first weeks of life. Evidence of constitutive TGF-β1-signalling was also observed in paediatric human AMs. TGF-β1-deficient AMs expressed enhanced levels of monocyte-attractant chemokines and, accordingly, Tgfb1ΔCD11c mice exposed to HDM throughout early life accumulated CCR2-dependent inflammatory CD11c+ mononuclear phagocytes into the airway niche that expressed the pro-allergic chemokine CCL8. Tgfb1ΔCD11c mice displayed augmented Th2, ILC2 and airway remodelling responses to HDM, which were ameliorated by blockade of the CCL8 receptor, CCR8. CONCLUSION: Our results highlight a causal relationship between AM maturity, chemokines and pathogenic immunity to environmental stimuli in early life and identify TGF-β1 as a key regulator of this.
Crick (Grant ID: 10126, Grant title: O' Garra FC001126)