Airway macrophage-intrinsic TGF-ß1 regulates pulmonary immunity during early-life allergen exposure.

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-ß-dependent postnatal development, but the role of AM maturation factors such as TGF-ß 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-ß1 regulates pathogenic immunity to inhaled allergen in early life. METHODS: Conditional knockout (Tgfb1ΔCD11c) mice, with TGF-ß1 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-ß1 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-ß1 signaling was also observed in pediatric human AMs. TGF-ß1-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. CONCLUSION: Our results highlight a causal relationship between AM maturity, chemokines, and pathogenic immunity to environmental stimuli in early life and identify TGF-ß1 as a key regulator of this.

Our evolving view of neutrophils in defining the pathology of chronic lung disease.

Neutrophils are critical components of the body's immune response to infection, being loaded with a potent arsenal of toxic mediators and displaying immense destructive capacity. Given the potential of neutrophils to impart extensive tissue damage, it is perhaps not surprising that when augmented these cells are also implicated in the pathology of inflammatory diseases. Prominent neutrophilic inflammation is a hallmark feature of patients with chronic lung diseases such as chronic obstructive pulmonary disease, severe asthma, bronchiectasis and cystic fibrosis, with their numbers frequently associating with worse prognosis. Accordingly, it is anticipated that neutrophils are central to the pathology of these diseases and represent an attractive therapeutic target. However, in many instances, evidence directly linking neutrophils to the pathology of disease has remained somewhat circumstantial and strategies that have looked to reduce neutrophilic inflammation in the clinic have proved largely disappointing. We have classically viewed neutrophils as somewhat crude, terminally differentiated, insular and homogeneous protagonists of pathology. However, it is now clear that this does not do the neutrophil justice, and we now recognize that these cells exhibit heterogeneity, a pronounced awareness of the localized environment and a remarkable capacity to interact with and modulate the behaviour of a multitude of cells, even exhibiting anti-inflammatory, pro-resolving and pro-repair functions. In this review, we discuss evidence for the role of neutrophils in chronic lung disease and how our evolving view of these cells may impact upon our perceived assessment of their contribution to disease pathology and efforts to target them therapeutically.

Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation.

Neutrophil mobilization, recruitment, and clearance must be tightly regulated as overexuberant neutrophilic inflammation is implicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophils therapeutically have failed to consider their pleiotropic functions and the implications of disrupting fundamental regulatory pathways that govern their turnover during homeostasis and inflammation. Using the house dust mite (HDM) model of allergic airway disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated T helper 2 (TH2) inflammation, epithelial remodeling, and airway resistance. Mechanistically, this was attributable to a marked increase in systemic granulocyte colony-stimulating factor (G-CSF) concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increased G-CSF augmented allergic sensitization in HDM-exposed animals by directly acting on airway type 2 innate lymphoid cells (ILC2s) to elicit cytokine production. Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool. By modeling the effects of neutrophil depletion, our studies have uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly, they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.