Branchett, William J. and Cook, James and Oliver, Robert A. and Bruno, Nicoletta and Walker, Simone A. and Stoelting, Helen and Mack, Matthias and O'Garra, Anne and Saglani, Sejal and Lloyd, Clare M. (2021) Airway macrophage-intrinsic TGF-beta 1 regulates pulmonary immunity during early-life allergen exposure. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 147 (5). pp. 1892-1906. ISSN 0091-6749, 1097-6825
Full text not available from this repository. (Request a copy)Abstract
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-beta-dependent postnatal development, but the role of AM maturation factors such as TGF-beta in controlling the threshold for pathogenic immune responses to inhaled allergens remains unclear. Objective: Our aim was to test the hypothesis that AM-derived TGF-beta 1 regulates pathogenic immunity to inhaled allergen in early life. Methods: Conditional knockout (Tgfb1(Delta CD11c)) mice, with TGF-beta 1 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. Results: AM-intrinsic TGF-beta 1 was redundant for initial population of the neonatal lung with AMs, but AMs from Tgfb1(Delta CD11c) mice failed to adopt a mature homeostatic AM phenotype in the first weeks of life. Evidence of constitutive TGF-beta 1 signaling was also observed in pediatric human AMs. TGF-beta 1-deficient AMs expressed enhanced levels of monocyte-attractant chemokines, and accordingly, Tgfb1(Delta DC11c) mice exposed to HDM throughout early life accumulated CCR2-dependent inflammatory CD11c(+) mononuclear phagocytes into the airway niche that expressed the proallergic chemokine CCL8. Tgfb1(Delta CD11c) mice displayed augmented T(H)2, group 2 innate lymphoid cell, and airway remodeling 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-beta 1 as a key regulator of this.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ALVEOLAR MACROPHAGES; TISSUE MACROPHAGES; FETAL MONOCYTES; DENDRITIC CELLS; 1ST WEEK; INFLAMMATION; MOUSE; HOMEOSTASIS; EXPRESSION; INFECTION; Asthma; type 2 immunity; neonate; TGF-beta; lung immunity; macrophage; monocyte; chemokine |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Sep 2022 09:41 |
| Last Modified: | 14 Sep 2022 09:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47451 |
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