29 results found
Branchett WJ, Cook J, Oliver RA, et al., 2021, Airway macrophage-intrinsic TGF-β1 regulates pulmonary immunity during early life allergen exposure, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 1892-1906, ISSN: 0091-6749
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.
Branchett WJ, Walker SA, Lloyd CM, 2021, Experimental Mouse Models of Asthma and Analysis of CD4 T Cells., Methods Mol Biol, Vol: 2285, Pages: 329-348
Asthma is a highly prevalent lung disease, characterized by airway dysfunction and chronic inflammation. Asthma occurs in both children and adults, but frequently originates in early life. Heterogeneous asthma phenotypes exist, but Th2 cells are key players in a large proportion of cases, while other CD4+ T cell subsets are also implicated in driving and limiting pathology. In this chapter, we describe methods for establishing allergic airway disease to model asthma in adult and neonatal mice, along with protocols for measuring key disease parameters and quantifying and phenotyping CD4+ T cell subtypes.
Ogger PP, Albers GJ, Hewitt RJ, et al., 2020, Itaconate controls the severity of pulmonary fibrosis, Science Immunology, Vol: 5, Pages: 1-13, ISSN: 2470-9468
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1-/- mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1-/- tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.
Branchett W, Stoelting H, Oliver R, et al., 2020, A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma, Journal of Allergy and Clinical Immunology, Vol: 145, Pages: 666-678.e9, ISSN: 0091-6749
BackgroundAlthough originally defined as a type 2 (T2) immune-mediated condition, non-T2 cytokines, such as IFN-γ and IL-17A, have been implicated in asthma pathogenesis, particularly severe disease. IL-10 regulates T helper (Th) cell phenotypes and can dampen T2 immunity to allergens, but its functions in controlling non-T2 cytokine responses in asthma are unclear. Objective: Determine how IL-10 regulates the balance of Th cell responses to inhaled allergen.MethodsAllergic airway disease (AAD) was induced in wild-type, IL-10 reporter and conditional IL-10 or IL-10 receptor α (IL-10Rα) knockout mice, by repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-γ signalling were disrupted using blocking antibodies.ResultsRepeated HDM inhalation induced a mixed IL-13/IL-17A response and accumulation of IL-10-producing FoxP3- effector CD4+ T cells in the lungs. Ablation of T cell-derived IL-10 increased the IFN-γ and IL-17A response to HDM, reducing IL-13 levels and airway eosinophilia without affecting IgE or airway hyperresponsiveness. The increased IFN-γ response could be recapitulated by IL-10Rα deletion in CD11c+ myeloid cells or local IL-10Rα blockade. Disruption of the T cell-myeloid IL-10 axis resulted in elevated pulmonary monocyte-derived dendritic cell numbers and increased IFN-γ-dependent expression of CXCR3 ligands by airway macrophages, suggestive of a feedforward loop of Th1 cell recruitment. Augmented IFN-γ responses in the HDM AAD model were accompanied by increased disruption of airway epithelium, which was reversed by therapeutic blockade of IFN-γ.ConclusionsIL-10 from effector T cells signals to CD11c+ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.
Byrne A, powell J, O'Sullivan B, et al., 2020, Dynamics of human monocytes and airway macrophages during healthy aging and post-transplant, Journal of Experimental Medicine, Vol: 217, Pages: 1-9, ISSN: 0022-1007
The ontogeny of airway macrophages (AMs) in human lung and their contribution to disease are poorly mapped out. In mice, aging is associated with an increasing proportion of peripherally, as opposed to perinatally derived AMs. We sought to understand AM ontogeny in human lung during healthy aging and after transplant. We characterized monocyte/macrophage populations from the peripheral blood and airways of healthy volunteers across infancy/childhood (2–12 yr), maturity (20–50 yr), and older adulthood (>50 yr). Single-cell RNA sequencing (scRNA-seq) was performed on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. During healthy aging, the proportions of blood and bronchoalveolar lavage (BAL) classical monocytes peak in adulthood and decline in older adults. scRNA-seq of BAL cells from lung transplant recipients indicates that after transplant, the majority of AMs are recipient derived. These data show that during aging, the peripheral monocyte phenotype is consistent with that found in the airways and, furthermore, that the majority of human AMs after transplant are derived from circulating monocytes.
Patel DF, Peiro T, Bruno N, et al., 2019, Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation, Science Immunology, Vol: 4, Pages: 1-18, ISSN: 2470-9468
Neutrophil mobilization, recruitmentand clearancemust be tightly regulated asover-exuberant neutrophilic inflammation isimplicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophilstherapeutically have failed to consider theirpleiotropic functions and theimplications of disrupting fundamental regulatory pathways that govern their turnover duringhomeostasisand inflammation.Using thehouse dust mite(HDM)model of allergic airways disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated TH2 inflammation, epithelial remodelling and airway resistance. Mechanistically, this was attributable to astriking increase insystemic G-CSF concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increasedG-CSF augmented allergic sensitization in HDM exposed animals bydirectly acting on airway ILC2s toelicitcytokine 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 modelling the effects of neutrophil depletion, our studies have therefore 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.
Allden SJ, Ogger PP, Ghai P, et al., 2019, The transferrin receptor CD71 delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 200, ISSN: 1073-449X
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defence of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor-1 (CD71)-expressing AMs in IPF is not known. OBJECTIVES: To assess the role of CD71 expressing AMs in the IPF-lung. METHODS: We utilized multi-parameter flow cytometry, gene expression analysis and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing, or lacking, CD71 in the BAL of patients with IPF or healthy controls. MEASUREMENTS AND MAIN RESULTS: There was a distinct increase in proportions of AMs lacking CD71 in IPF patients in comparison to healthy controls. Levels of BAL transferrin were enhanced in IPF-BAL and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally and transcriptionally distinct, with CD71- AMs characterised by reduced expression of markers of macrophage maturity, impaired phagocytosis and enhanced expression of pro-fibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. CONCLUSIONS: Taken together these data highlight how CD71 delineates AM subsets which play distinct roles in IPF and furthermore, CD71- AMs may be an important pathogenic component of fibrotic lung disease.
Lloyd C, Puttur F, Denney L, et al., 2019, Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans, Science Immunology, Vol: 4, ISSN: 2470-9468
Group 2 innate lymphoid cells (ILC2s) are enriched in mucosal tissues (e.g., lung) and respond to epithelial cell–derived cytokines initiating type 2 inflammation. During inflammation, ILC2 numbers are increased in the lung. However, the mechanisms controlling ILC2 trafficking and motility within inflamed lungs remain unclear and are crucial for understanding ILC2 function in pulmonary immunity. Using several approaches, including lung intravital microscopy, we demonstrate that pulmonary ILC2s are highly dynamic, exhibit amoeboid-like movement, and aggregate in the lung peribronchial and perivascular spaces. They express distinct chemokine receptors, including CCR8, and actively home to CCL8 deposits located around the airway epithelium. Within lung tissue, ILC2s were particularly motile in extracellular matrix–enriched regions. We show that collagen-I drives ILC2 to markedly change their morphology by remodeling their actin cytoskeleton to promote environmental exploration critical for regulating eosinophilic inflammation. Our study provides previously unappreciated insights into ILC2 migratory patterns during inflammation and highlights the importance of environmental guidance cues in the lung in controlling ILC2 dynamics.
Uwadiae F, Pyle C, Walker S, et al., 2019, Targeting the ICOS/ICOS-L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease, Allergy, Vol: 74, Pages: 650-662, ISSN: 0105-4538
BackgroundAllergic asthma is characterized by chronic inflammation and remodelling of the airways, associated with dysregulated type 2 immune responses and allergen‐specific IgE. T follicular helper cells (TFH) are crucial in T‐dependent B cell responses and have been implicated in allergic airway disease (AAD). TFH, unlike other CD4+ T cells are uniquely reliant on continuous ICOS signalling to maintain their phenotype after T cell priming, therefore disrupting this signal can impair TFH responses. However, the contribution of TFH to disease during chronic aero‐allergen exposure and the therapeutic potential of targeting these cells has not been evaluated.MethodsTo establish AAD, female BALB/c mice were repeatedly exposed to house dust mite or Alternaria alternata three times a week for up to 5 weeks. To examine the impact of TFH on AAD, mice were allergen exposed for 5 weeks and co‐administered anti‐ICOS‐Ligand targeted antibodies, 3 times for the last 2 weeks.ResultsTFH were first observed in the lung draining lymph nodes and with further exposure were also found locally within the lungs. TFH accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted TFH but did not affect the differentiation of other CD4+ T cell subsets. This reduced GC responses, allergen‐specific IgE, inflammation, pulmonary IL‐13 and airway hyper‐responsiveness.ConclusionsTFH are crucial in the regulation of AAD and the ICOS/ICOS‐L pathway could represent a novel therapeutic target in allergic asthma.
Reynolds CJ, Quigley K, Cheng X, et al., 2018, Lung defense through interleukin-8 carries a cost of chronic lung remodeling and impaired function, American Journal of Respiratory Cell and Molecular Biology, Vol: 59, Pages: 557-571, ISSN: 1044-1549
RATIONALE: IL-8 dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases including COPD, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible pathologic, changes associated with elevated levels of IL-8 in the lung. OBJECTIVES: To better understand the duality of IL-8 dependent host immunity to bacterial infection and lung pathology, we targeted human IL-8 to express transgenically in murine bronchial epithelium, investigating the impact of over-expression on lung bacterial clearance, host immunity, lung pathology and function. MEASUREMENTS AND MAIN RESULTS: Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation, activation and chemtoaxis. There was enhanced protection from challenge with Pseudomonas aeruginosa and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL2 and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen, OprF, indicating a regulatory T cell phenotype. However, this enhanced bacterial immunity comes at the high price of progressive lung remodelling, with increased inflammation, mucus hyper-secretion, and fibrosis. There is increased expression of Ccl3 and reduced expressioh of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all resulting in impaired lung function with reduced compliance, increased resistance and bronchial hyperreactivity measured by whole body plethysmography. CONCLUSIONS: IL-8 over-expression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodelling and damaged tight junctions, leading to impaired lung function.
Saglani S, Gregory LG, Manghera AK, et al., 2018, Inception of early life allergen induced airway hyperresponsiveness is reliant on IL-13+CD4+ T cells, Science Immunology, Vol: 3, Pages: 1-12, ISSN: 2470-9468
Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or Alternaria alternata] exposure from day 3 of life resulted in significantly increased pulmonary IL-13+CD4+ T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary LinnegCD45+CD90+IL-13+ type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4creIL-13 KO mice (lacking IL-13+CD4+ T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13+ ILCs. Moreover, neonatal mice were protected from AHR when inhaled Acinetobacter lwoffii (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. A. lwoffii blocked the expansion of pulmonary IL-13+CD4+ T cells, whereas IL-13+ ILCs and IL-33 remained elevated. Administration of A. lwoffii mirrored the findings from the CD4creIL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13+CD4+ T cells, rather than IL-13+ ILCs or IL-33, are critical for inception of allergic AHR in early life.
Patel D, Peiro T, Shoemark A, et al., 2018, An extracellular matrix fragment drives epithelial remodeling and airway hyper-responsiveness, Science Translational Medicine, Vol: 10, Pages: 1-13, ISSN: 1946-6234
It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A4 hydrolase (LTA4H) mediates opposing proinflammatory and anti-inflammatory activities, through the generation of leukotriene B4 (LTB4) and degradation of proneutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show that abrogation of LTB4 signaling ameliorated inflammation and airway hyperresponsiveness (AHR) in a murine asthma model, yet global loss of LTA4H exacerbated AHR, despite the absence of LTB4. This exacerbated AHR was attributable to a neutrophil-independent capacity of PGP to promote pathological airway epithelial remodeling. Thus, we demonstrate a disconnect between airway inflammation and AHR and the ability of a matrikine to promote an epithelial remodeling phenotype that negatively affects lung function. Subsequently, we show that substantial quantities of PGP are detectable in the sputum of moderate-severe asthmatics in two distinct cohorts of patients. These studies have implications for our understanding of remodeling phenotypes in asthma and may rationalize the failure of LTA4H inhibitors in the clinic.
Zhang Y, Poobalasingam T, Yates LL, et al., 2018, Manipulation of Dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma, Disease Models and Mechanisms, Vol: 11, ISSN: 1754-8403
We previously identified dipeptidylpeptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies.
Poobalasingam T, Yates LL, Walker SA, et al., 2017, Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair, Disease Models & Mechanisms, Vol: 10, Pages: 409-423, ISSN: 1754-8403
Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SC
Byrne AJ, Weiss M, Mathie SA, et al., 2016, A critical role for IRF5 in regulating allergic airway inflammation, Mucosal Immunology, Vol: 10, Pages: 716-726, ISSN: 1935-3456
Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of theexpression of pro-inflammatory cytokine and responses to infection, however its role in regulatingpulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviralvector-driven overexpression and adoptive transfer approaches to interrogate the role of IRF5 inpulmonary immunity and during challenge with the aero-allergen, house dust mite. Global IRF5deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5was also essential for effective responses to inhaled allergen, controlling airway hyper-responsiveness, mucus secretion and eosinophilic inflammation. Adoptive transfer of IRF5-deficient alveolar macrophages into the WT pulmonary milieu was sufficient to drive airwayhyper-reactivity, at baseline or following antigen challenge. These data identify IRF5-expressingmacrophages as a key component of the immune defence of the airways. Manipulation of IRF5activity in the lung could therefore be a viable strategy for the redirection of pulmonary immuneresponses and thus, the treatment of lung disorders.
Löser S, Gregory LG, Zhang Y, et al., 2016, Pulmonary ORMDL3 is critical for induction of Alternaria induced allergic airways disease, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1496-1507.e3, ISSN: 1097-6825
BACKGROUND: Genome-wide association studies have identified the ORMDL3 (ORM (yeast)-like protein isoform 3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. OBJECTIVE: We sought to investigate in vivo the functional role of ORMDL3 in disease inception. METHODS: An Ormdl3 deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata determined. An adeno-associated viral vector was also utilized to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 KO mice. RESULTS: Ormdl3 knock-out mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response and ORMDL3 was found to play a critical role in driving the ATF6 mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum-associated degradation pathway. Additionally ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen-induced allergic airways disease. CONCLUSIONS: This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.
Denney L, Byrne A, Shea T, et al., 2015, Pulmonary epithelial cell-derived cytokine TGF-β1 Is a critical cofactor for enhanced innate lymphoid cell function, Immunity, Vol: 43, Pages: 945-958, ISSN: 1097-4180
Epithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions.
Castanhinha S, Sherburn RT, Walker SA, et al., 2015, Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 312-322.e7, ISSN: 1097-6825
Background: The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. Objective: We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. Methods: Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n= 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. Results: Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P= .006), higher total IgE levels (637 vs 177 IU/mL, P= .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P= .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13+ innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2-/- mice lacking a functional receptor for IL-33. Conclusion: Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33-mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.
Lee DC, Walker SA, Byrne AJ, et al., 2015, Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life., Thorax, ISSN: 1468-3296
Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model.
Johnson JR, Folestad E, Rowley JE, et al., 2015, Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 308, Pages: L658-L671, ISSN: 1040-0605
Denney L, Gregory LG, Shea TJ, et al., 2014, Pulmonary epithelial-derived TGF-beta 1 is critical for the inception of innate lymphoid cell mediated allergic airways disease, Publisher: WILEY-BLACKWELL, Pages: 41-41, ISSN: 0019-2805
Loeser S, Zhang Y, Gregory L, et al., 2014, Novel insights into the in vivo function of Ormdl3 - a gene associated with the onset of childhood asthma, IMMUNOLOGY, Vol: 143, Pages: 59-59, ISSN: 0019-2805
Mathie SA, Dixon KL, Walker SA, et al., 2014, Alveolar macrophages are sentinels of murine pulmonary homeostasis following inhaled antigen challenge., Allergy, Vol: 70, Pages: 80-89, ISSN: 1398-9995
Alveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma.
Vasiliou JE, Lui S, Walker SA, et al., 2014, Vitamin D deficiency induces Th2 skewing and eosinophilia in neonatal allergic airways disease, ALLERGY, Vol: 69, Pages: 1380-1389, ISSN: 0105-4538
Snelgrove RJ, Gregory LG, Peiro T, et al., 2014, Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations, Journal of Allergy and Clinical Immunology, Vol: 134, Pages: 583-592.e6, ISSN: 1097-6825
BackgroundThe fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear.ObjectiveWe sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation.MethodsIL-33 levels were quantified in wild-type and ST2−/− mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria, and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later.ResultsAlternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease–IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model.
Saglani S, Lui S, Ullmann N, et al., 2013, IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 132, Pages: 676-+, ISSN: 0091-6749
Gregory LG, Jones CP, Walker SA, et al., 2013, IL-25 drives remodelling in allergic airways disease induced by house dust mite, THORAX, Vol: 68, Pages: 82-90, ISSN: 0040-6376
Vasiliou J, Lui S, Walker S, et al., 2011, Effects of vitamin D deficiency during early life on the development of neonatal house dust mite induced allergic airways disease, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 204-204, ISSN: 0019-2805
Gregory LG, Mathie SA, Walker SA, et al., 2010, Overexpression of Smad2 Drives House Dust Mite-mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 182, Pages: 143-154, ISSN: 1073-449X
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