Publications
300 results found
Davies ER, Denney L, Wandel M, et al., 2019, Regulation of ectodomain shedding of ADAM33 in vitro and in vivo, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 2281-2284.e3, ISSN: 0091-6749
Oksel C, Custovic A, Granell R, et al., 2019, Causes of variability in latent phenotypes of childhood wheeze, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 1783-1790.e11, ISSN: 0091-6749
BackgroundLatent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies.ObjectiveWe sought to investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood.MethodsWe used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size and data collection age and intervals on the results and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23 to 24 years.ResultsA relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (eg, number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157, and 166). The proportion of asthmatic patients at age 23 to 24 years differed between phenotypes, whereas lung function was lower among persistent wheezers.ConclusionsSample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by using LCA in longitudinal data.
Robinson PFM, Pattaroni C, Cook J, et al., 2019, Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 1607-1610.e, ISSN: 0091-6749
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.
Branchett W, Lloyd C, 2019, Regulatory cytokine function in the respiratory tract, Mucosal Immunology, Vol: 12, Pages: 589-600, ISSN: 1933-0219
The respiratory tract is an important site of immune regulation; required to allow protective immunity against pathogens, while minimizing tissue damage and avoiding aberrant inflammatory responses to inhaled allergens. Several cell types work in concert to control pulmonary immune responses and maintain tolerance in the respiratory tract, including regulatory and effector T cells, airway and interstitial macrophages, dendritic cells and the airway epithelium. The cytokines transforming growth factor β (TGF-β), interleukin (IL-) 10, IL-27 and IL-35 are key coordinators of immune regulation in tissues such as the lung. Here, we discuss the role of these cytokines during respiratory infection and allergic airway disease, highlighting the critical importance of cellular source and immunological context for the effects of these cytokines in vivo.
Agace W, Cerf-Bensussan N, Lloyd C, et al., 2019, Thank you to our reviewers!, Mucosal Immunology, Vol: 12, Pages: 293-295, ISSN: 1933-0219
Gregory L, Lloyd C, Puttur F, 2019, Airway macrophages as the guardians of tissue repair in the lung, Immunology and Cell Biology, ISSN: 1440-1711
Zhang Y, Willis-Owen S, Spiegel S, et al., 2019, The ORMDL3 asthma gene regulates ICAM1 and has multiple effects on cellular inflammation, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 478-488, ISSN: 1073-449X
Rationale: Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 expression. The locus influences disease severity and the frequency of human rhinovirus (HRV) initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase (SPT), but its role in inflammation is incompletely understood. Objectives: To investigate the role of ORMDL3 in cellular inflammation. Methods: We modelled time-series of IL1B-induced inflammation in A549 cells, using cytokine production as outputs and testing effects of ORMDL3 siRNA knockdown, ORMDL3 overexpression, and the SPT inhibitor myriocin. We replicated selected findings in normal human bronchial epithelial (NHBE) cells. Cytokine and metabolite levels were analysed by ANOVA. Transcript abundances were analysed by group means parameterisation, controlling the false discovery rate (FDR) below 0.05. Measurements and Main Results: Silencing ORMDL3 led to steroid-independent reduction of IL6 and IL8 release and reduced ER stress after IL1B. Overexpression and myriocin conversely augmented cytokine release. Knockdown reduced expression of genes regulating host-pathogen interactions, stress responses and ubiquitination: in particular ORMDL3 knockdown strongly reduced expression of the HRV receptor ICAM1. Silencing led to changes in levels of transcripts and metabolites integral to glycolysis. Increased levels of ceramides and the immune mediator sphingosine-1-P (S1P) were also observed. Conclusions: The results show ORMDL3 has pleiotropic effects during cellular inflammation, consistent with its substantial genetic influence on childhood asthma. Actions on ICAM1 provide a mechanism for the locus to confer susceptibility to HRV-induced asthma.
Saglani S, Lloyd CM, 2019, 43 - The Immunopathogenesis of Asthma, Kendig's Disorders of the Respiratory Tract in Children, Pages: 665-676.e3, ISBN: 9780323448871
Asthma occurs as a result of the interplay of genetic susceptibility and environmental influences on the developing lungs and immune system. Asthma in children is predominantly associated with the development of allergic sensitization and the pathological features of eosinophilic airway inflammation and structural airway wall changes, collectively termed airway remodeling. The clinical manifestation of disease is heterogeneous but includes symptoms of breathlessness and wheeze, which result from bronchoconstriction. Acute attacks in children commonly result from respiratory infection, with repeated episodes of infection with rhinovirus and respiratory syncytial virus in early life being especially associated with the risk of recurrent wheezing and asthma in children who also develop early allergic sensitization and have a genetic susceptibility. The focus of this chapter is to discuss the basic immunological mechanisms that drive the pathophysiology of asthma, with specific focus on the close interactions between innate and adaptive immune responses in driving disease. The immunopathology of specific clinical manifestations of disease, including exacerbations and preschool wheezing disorders, will also be discussed, and mechanisms that are unique to the developing pediatric airway and that cannot be extrapolated from adult disease will be highlighted.
Saglani S, Lloyd CM, Bush A, 2019, Biology and Assessment of Airway Inflammation, Kendig's Disorders of the Respiratory Tract in Children, Pages: 101-119.e4, ISBN: 9780323448871
The nature and development airway inflammation may be driven by numerous factors, including pathogenic infections, pollution, or even relatively innocuous inhaled particles, such as allergens. A robust inflammatory response is essential to fight pathogens, but both active inflammation and efficient resolution are equally important. The failure of resolution or persistent proinflammatory immune responses results in chronic inflammatory airway diseases. These may be characterized by persistent neutrophilic inflammation, as is the case in cystic fibrosis and chronic suppurative lung diseases, or persistent eosinophilia, as is seen in allergic asthma. It is essential to accurately undertake an assessment of the airway inflammatory phenotype in chronic airways diseases to allow an understanding of the mechanisms mediating disease and identify appropriate therapeutic targets. It is also becoming increasingly important to phenotype airway inflammation in individual patients to allow targeted treatment as we move towards personalized therapies. This chapter will discuss what is known about the mechanisms driving chronic inflammatory airways diseases in children and provide an update on the methods used to investigate airway inflammation invasively and noninvasively in patients to allow phenotype driven and targeted therapies.
Saglani S, Lloyd CM, 2019, The Immunopathogenesis of Asthma, Kendig's Disorders of the Respiratory Tract in Children, Publisher: Elsevier, Pages: 665-676.e3, ISBN: 9780323448871
Robinson PF, Pattaroni C, Cook J, et al., 2019, Lower Airway Microbiota Associates with Inflammatory Phenotype in Severe Preschool Wheeze, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Snelgrove RJ, Patel DF, Patel T, et al., 2018, The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent?, Clinical and Experimental Allergy, Vol: 48, Pages: 1275-1285, ISSN: 0954-7894
Whilst severe asthma has classically been categorized as a predominantly Th2-driven pathology, there has in recent years been a paradigm shift with the realization that it is a heterogeneous disease that may manifest with quite disparate underlying inflammatory and remodelling profiles. A subset of asthmatics, particularly those with a severe, corticosteroid refractory disease, present with a prominent neutrophilic component. Given the potential of neutrophils to impart extensive tissue damage and promote inflammation, it has been anticipated that these cells are closely implicated in the underlying pathophysiology of severe asthma. However, uncertainty persists as to why the neutrophil is present in the asthmatic lung and what precisely it is doing there, with evidence supporting its role as a protagonist of pathology being primarily circumstantial. Furthermore, our view of the neutrophil as a primitive, indiscriminate killer has evolved with the realization that neutrophils can exhibit a marked anti-inflammatory, pro-resolving and wound healing capacity. We suggest that the neutrophil likely exhibits pleiotropic and potentially conflicting roles in defining asthma pathophysiology-some almost certainly detrimental and some potentially beneficial-with context, timing and location all critical confounders. Accordingly, indiscriminate blockade of neutrophils with a broad sword approach is unlikely to be the answer, but rather we should first seek to understand their complex and multifaceted roles in the disease state and then target them with the same subtleties and specificity that they themselves exhibit.
Benn CS, Hornef M, Naik S, et al., 2018, Immunity in the Very Young: Challenges and Opportunities, IMMUNITY, Vol: 49, Pages: 377-378, ISSN: 1074-7613
Ogger P, Maher T, Lloyd C, et al., 2018, Distinct metabolic alterations in airway macrophages during pulmonary fibrosis, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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.
Snelgrove RJ, Lloyd CM, 2018, Tasting type 2 inflammation in the airways, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 403-404, ISSN: 0091-6749
Lloyd CM, Snelgrove RJ, 2018, Type 2 immunity: expanding our view., Science Immunology, Vol: 3, ISSN: 2470-9468
The classical vision of type 2 immune reactions is that they are characterized by a distinct cellular and cytokine repertoire that is critical for host resistance against helminthic worm infections but, when dysregulated, may cause atopic reactions that result in conditions such as asthma, rhinitis, dermatitis, and anaphylaxis. In this traditional view, the type 2 response is categorized as an adaptive immune response with differentiated T helper cells taking center stage, driving eosinophil recruitment and immunoglobulin production via the secretion of a distinct repertoire of cytokines that include interleukin-4 (IL-4), IL-5, and IL-13. The recent discovery of a group of innate cells that has the capacity to secrete copious amounts of type 2 cytokines, potentially in the absence of adaptive immunity, has reignited interest in type 2 biology. The discovery that these innate lymphoid cells and type 2 cytokines are involved in diverse biological processes-including wound healing, control of metabolic homeostasis, and temperature-has considerably changed our view of type 2 responses and the cytokines, chemokines, and receptors that regulate these responses.
Lloyd CM, Harker JA, 2018, Epigenetic control of interleukin-9 in asthma, New England Journal of Medicine, Vol: 379, Pages: 87-89, ISSN: 0028-4793
Meiners S, Lloyd C, Chambers RC, 2018, Cell-matrix interactions in lung disease and regeneration: ERS Lung Science Conference 2018 report, European Respiratory Review, Vol: 27, ISSN: 0905-9180
Turner S, Custovic A, Ghazal P, et al., 2018, Pulmonary epithelial barrier and immunological functions at birth and in early life - key determinants of the development of asthma? A description of the protocol for the Breathing Together study [version 1; peer review: 2 approved], Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Background. Childhood asthma is a common complex condition whose aetiology is thought to involve gene-environment interactions in early life occurring at the airway epithelium, associated with immune dysmaturation. It is not clear if abnormal airway epithelium cell (AEC) and cellular immune system functions associated with asthma are primary or secondary. To explore this, we will (i) recruit a birth cohort and observe the evolution of respiratory symptoms; (ii) recruit children with and without asthma symptoms; and (iii) use existing data from children in established STELAR birth cohorts. Novel pathways identified in the birth cohort will be sought in the children with established disease. Our over-arching hypothesis is that epithelium function is abnormal at birth in babies who subsequently develop asthma and progression is driven by abnormal interactions between the epithelium, genetic factors, the developing immune system, and the microbiome in the first years of life.Methods. One thousand babies will be recruited and nasal AEC collected at 5-10 days after birth for culture. Transcriptomes in AEC and blood leukocytes and the upper airway microbiome will be determined in babies and again at one and three years of age. In a subset of 100 individuals, AEC transcriptomes and microbiomes will also be assessed at three and six months. Individuals will be assigned a wheeze category at age three years. In a cross sectional study, 300 asthmatic and healthy children aged 1 to 16 years will have nasal and bronchial AEC collected for culture and transcriptome analysis, leukocyte transcriptome analysis, and upper and lower airway microbiomes ascertained. Genetic variants associated with asthma symptoms will be confirmed in the STELAR cohorts. Conclusions. This study is the first to comprehensively study the temporal relationship between aberrant AEC and immune cell function and asthma symptoms in the context of early gene-microbiome interactions.
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.
Uwadiae FI, Pyle CJ, Walker SA, et al., 2018, Therapeutic ICOS blockade reduces T follicular helper cells and improves allergic airway disease
<jats:title>ABSTRACT</jats:title><jats:p>Allergic asthma is a disease of chronic airway inflammation and remodelling, characterised by a dysregulated type 2 response and allergen-specific IgE. T follicular helper cells (T<jats:sub>FH</jats:sub>) are critical to antibody production and have recently been implicated in allergic airway disease (AAD) pathogenesis. The role of T<jats:sub>FH</jats:sub>in established disease and the therapeutic potential of targeting them are however not fully understood. Using two aeroallergen driven murine models of chronic AAD, T<jats:sub>FH</jats:sub>were first identified in the lung draining lymph nodes but with prolonged exposure were present in the lung itself. Sustained allergen exposure led to the accumulation of T<jats:sub>FH</jats:sub>, and concomitant development of germinal centre B cells. Blockade of Inducible T cell co-stimulator (ICOS) signalling during established AAD depleted T<jats:sub>FH</jats:sub>without adversely affecting the differentiation of other CD4<jats:sup>+</jats:sup>T cell subsets. This resulted in impaired germinal centre responses, reduced allergen specific IgE and ameliorated inflammation and airway hyper-responsiveness, including reduced pulmonary IL-13. T<jats:sub>FH</jats:sub>did not however appear to produce IL-13 directly, suggesting they indirectly promote type-2 inflammation in the lungs. These data show that T<jats:sub>FH</jats:sub>play a pivotal role in the regulation of AAD and that targeting the ICOS-L pathway could represent a novel therapeutic approach in this disease.</jats:p>
Cook J, Martin-Alonso A, Sanghani N, et al., 2018, Children with Pre-School Wheeze Have Neutrophilic Airway Inflammation Associated with Bacteria and Viruses During Periods of Clinical Stability, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
O'Reilly PJ, Ding Q, Akthar S, et al., 2017, Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis, JCI INSIGHT, Vol: 2, ISSN: 2379-3708
The neutrophil chemoattractant proline-glycine-proline (PGP) is generated from collagen by matrix metalloproteinase-8/9 (MMP-8/9) and prolyl endopeptidase (PE), and it is concomitantly degraded by extracellular leukotriene A4 hydrolase (LTA4H) to limit neutrophilia. Components of cigarette smoke can acetylate PGP, yielding a species (AcPGP) that is resistant to LTA4H-mediated degradation and can, thus, support a sustained neutrophilia. In this study, we sought to elucidate if an antiinflammatory system existed to degrade AcPGP that is analogous to the PGP-LTA4H axis. We demonstrate that AcPGP is degraded through a previously unidentified action of the enzyme angiotensin-converting enzyme (ACE). Pulmonary ACE is elevated during episodes of acute inflammation, as a consequence of enhanced vascular permeability, to ensure the efficient degradation of AcPGP. Conversely, we suggest that this pathway is aberrant in chronic obstructive pulmonary disease (COPD) enabling the accumulation of AcPGP. Consequently, we identify a potentially novel protective role for AcPGP in limiting pulmonary fibrosis and suggest the pathogenic function attributed to ACE in idiopathic pulmonary fibrosis (IPF) to be a consequence of overzealous AcPGP degradation. Thus, AcPGP seemingly has very divergent roles: it is pathogenic in its capacity to drive neutrophilic inflammation and matrix degradation in the context of COPD, but it is protective in its capacity to limit fibrosis in IPF.
Peiró T, Patel DF, Akthar S, et al., 2017, Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection, Thorax, Vol: 73, Pages: 546-556, ISSN: 1468-3296
Background Alveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1β release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed.Methods Mice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody.Results Influenza elicited a robust IL-1β release that correlated (r=0.6849; p<0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1β during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1β in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1β from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils.Conclusions Neutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.
denney L, Branchett W, Gregory L, et al., 2017, Epithelial derived TGF-β1 acts as a pro-viral factor in the lung during influenza A infection, Mucosal Immunology, Vol: 11, Pages: 523-535, ISSN: 1933-0219
Mucosal surfaces are under constant bombardment from potentially antigenic particles and so must maintain a balance between homeostasis and inappropriate immune activation and consequent pathology. Epithelial cells have a vital role orchestrating pulmonary homeostasis and defense against pathogens. TGF-β regulates an array of immune responses—both inflammatory and regulatory—however, its function is highly location- and context-dependent. We demonstrate that epithelial-derived TGF-β acts as a pro-viral factor suppressing early immune responses during influenza A infection. Mice specifically lacking bronchial epithelial TGF-β1 (epTGFβKO) displayed marked protection from influenza-induced weight loss, airway inflammation, and pathology. However, protection from influenza-induced pathology was not associated with a heightened lymphocytic immune response. In contrast, the kinetics of interferon beta (IFNβ) release into the airways was significantly enhanced in epTGFβKO mice compared with control mice, with elevated IFNβ on day 1 in epTGFβKO compared with control mice. This induced a heighted antiviral state resulting in impaired viral replication in epTGFβKO mice. Thus, epithelial-derived TGF-β acts to suppress early IFNβ responses leading to increased viral burden and pathology. This study demonstrates the importance of the local epithelial microenvironmental niche in shaping initial immune responses to viral infection and controlling host disease.
Loser S, Lloyd CM, Gregory LG, 2017, Epithelial perviousness in allergic airways disease Reply, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 140, Pages: 1211-1212, ISSN: 0091-6749
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Pavord ID, Beasley R, Agusti A, et al., 2017, After asthma: redefining airways diseases., Lancet, Vol: 391, Pages: 350-400, ISSN: 0140-6736
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