Airway macrophage-intrinsic TGF-β1 regulates pulmonary immunity during early-life allergen exposure

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-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 Our aim was to test the hypothesis that AM-derived TGF-β1 regulates pathogenic immunity to inhaled allergen in early life. Methods Conditional knockout ( Tgfb1 ΔCD11c ) 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. Results AM-intrinsic TGF-β1 was redundant for initial population of the neonatal lung with AMs, but AMs from Tgfb1 ΔCD11c 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, Tgfb1 ΔCD11c 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 ΔCD11c 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-β1 as a key regulator of this.

The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

“…Consequently, genetic disruption of Itgb6 , which encodes integrin β6, leads to development of emphysema due to excessive production of MMP12 by dysfunctional AlvMϕs; a phenotype that can be rescued by constitutive expression of TGFβ1 121 , 122 . Human AMϕs are known to have a gene signature consistent with TGFβR signalling 123 and myeloid-specific deletion of TGFβR in mice leads to aborted AlvMϕ development, demonstrating a need for cell intrinsic TGFβR for this process 124 , 125 . Interestingly, although many cells can produce TGFβ, macrophages themselves are thought to be an important source 123 , 124 .…”

“…Human AMϕs are known to have a gene signature consistent with TGFβR signalling 123 and myeloid-specific deletion of TGFβR in mice leads to aborted AlvMϕ development, demonstrating a need for cell intrinsic TGFβR for this process 124 , 125 . Interestingly, although many cells can produce TGFβ, macrophages themselves are thought to be an important source 123 , 124 . Moreover, AlvMϕs can facilitate integrin-mediated release of active TGFβ through production of amphiregulin, at least in the context of helminth infection 126 .…”

Diversity of Macrophages in Lung Homeostasis and Diseases

“…Apoptotic cell engulfment in TR-AMs promotes the production of the regulatory T cell-inducing molecule retinoic acid, which impacts the development of allergen-induced asthmatic airway inflammation (76). Intrinsic TGF-b1 in TR-AMs is essential for TR-AM maturation and is also involved in the control of allergic reactions (59). TGF-b1-deficient AMs expressed enhanced levels of monocyte-attractant chemokines and displayed augmented type II inflammation to house dust mite (59).…”

“…Intrinsic TGF-b1 in TR-AMs is essential for TR-AM maturation and is also involved in the control of allergic reactions (59). TGF-b1-deficient AMs expressed enhanced levels of monocyte-attractant chemokines and displayed augmented type II inflammation to house dust mite (59). Lung macrophage mannose receptor (MRC1/CD206) also have functions in protection against allergen-induced lung inflammation and Mrc1-/-mice had an exacerbated lung inflammation that caused by allergen (79).…”

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

“…ILC2s are an important in vivo source of CCL1 and support their proliferation and effector functions via an auto-regulatory positive feedback loop ( 26 ). By contrast, CCL8 was shown to be primarily produced by inflammatory CD11c + mononuclear phagocytes ( 27 ) and controls the local positioning of ILC2s within the lung during type 2-mediated inflammation ( 28 ).…”