Abstract
BackgroundEarly 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.ObjectiveOur aim was to test the hypothesis that AM-derived TGF-β1 regulates pathogenic immunity to inhaled allergen in early life.MethodsConditional knockout (Tgfb1ΔCD11c) mice, with TGF-β1 deficiency in AMs and other CD11c+ cells, were analyzed throughout early life and following neonatal house dust mite (HDM) inhalation. The roles of specific chemokine receptors were determined by using in vivo blocking antibodies.ResultsAM-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 signaling was also observed in pediatric 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 proallergic chemokine CCL8. Tgfb1ΔCD11c mice displayed augmented TH2, group 2 innate lymphoid cell, and airway remodeling responses to HDM, which were ameliorated by blockade of the CCL8 receptor CCR8.ConclusionOur 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.
Highlights
Life represents a major risk window for asthma development
CD11c1Siglec F1 airway macrophage (AM) were present at postnatal day 3 (P3) in Tgfb1fl/fl littermate control mice, and their numbers remained similar from P7 to adulthood (8-10 weeks [Fig 1, A and see Fig E1, B])
Expression of Il1b was decreased in Tgfb1DCD11c mice compared with in their Tgfb1fl/fl littermates after house dust mite (HDM) treatment, with a trend toward decrease in Il12a expression. These results do not support increased proinflammatory cytokine production as a correlate of the more severe airway disease (AAD) observed in Tgfb1DCD11c mice exposed to HDM during early life. Because both AMs and Siglec F–CD11c1MHC class II1CD641 inflammatory mononuclear phagocyte (MP), which are likely to encompass some of the SigF– MPs observed in our model, produce proallergic chemokines during HDM-driven AAD,[14,15,22] we proposed that inflammatory CD11c1 MPs could promote an elevated level of type 2 (T2) immunity in HDM-treated Tgfb1DCD11c mice by chemokine production
Summary
Life represents a major risk window for asthma development. 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-b–dependent postnatal development, but the role of AM maturation factors such as TGF-b in controlling the threshold for pathogenic immune responses to inhaled allergens remains unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
