6 results found
Turnbull A, Pyle C, Patel D, et al., 2020, Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, Vol: 19, Pages: 40-48, ISSN: 1569-1993
BackgroundProline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.MethodsBroncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed.ResultsWhilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.ConclusionsA striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.
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.
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.
Uwadiae FI, Pyle CJ, Walker SA, et al., 2018, Therapeutic ICOS blockade reduces T follicular helper cells and improves allergic airway disease, Publisher: Cold Spring Harbor Laboratory
<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>
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.
Pyle CJ, Uwadiae FI, Swieboda DP, et al., 2017, Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology., PLoS Pathogens, Vol: 13, ISSN: 1553-7366
Interleukin-6 is a pleiotropic, pro-inflammatory cytokine that can promote both innate and adaptive immune responses. In humans with respiratory virus infections, such as Respiratory Syncytial Virus (RSV), elevated concentrations of IL-6 are associated with more severe disease. In contrast the polymorphisms in the Il6 promoter which favour lower IL-6 production are associated with increased risk of both RSV and Rhinovirus infections. To determine the precise contribution of IL-6 to protection and pathology we used murine models of respiratory virus infection. RSV infection resulted in increased IL-6 production both in the airways and systemically which remained heightened for at least 2 weeks. IL-6 depletion early, but not late, during RSV or Influenza A virus infection resulted in significantly increased disease associated with an influx of virus specific TH1 and cytotoxic CD8+ T cells, whilst not affecting viral clearance. IL-6 acted by driving production of the immunoregulatory cytokine IL-27 by macrophages and monocytes, which in turn promoted the local maturation of regulatory T cells. Concordantly IL-27 was necessary to regulate TH1 responses in the lungs, and sufficient to limit RSV induced disease. Overall we found that during respiratory virus infection the prototypic inflammatory cytokine IL-6 is a critical anti-inflammatory regulator of viral induced immunopathology in the respiratory tract through its induction of IL-27.
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