Mϕs are the main innate immune cells in the lung at homeostasis, with important roles in host defence and immune modulation. Alveolar Mϕs (AMs) and interstitial Mϕs (IMs) are the two lung Mϕ subsets, ...so called according to the sites they reside in. These subsets are also defined by their origins and immunological microenvironment, which endow these cells with distinct features and plasticity. This review summarizes the latest definitions and functions of lung Mϕs during homeostasis and provides exemplar of their divergent roles in lung fibrosis.
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Review describes the latest definitions and functions of lung macrophages during homeostasis and provides examples of their different roles in the development and progression of lung fibrosis.
The respiratory epithelium is the major interface between the environment and the host. Sophisticated barrier, sensing, anti-microbial and immune regulatory mechanisms have evolved to help maintain ...homeostasis and to defend the lung against foreign substances and pathogens. During influenza virus infection, these specialised structural cells and populations of resident immune cells come together to mount the first response to the virus, one which would play a significant role in the immediate and long term outcome of the infection. In this review, we focus on the immune defence machinery of the respiratory epithelium and briefly explore how it repairs and regenerates after infection.
Children with STRA and a disease control group of children with recurrent lower respiratory tract infections (LRTIs), but no atopy or asthma, undergoing clinically indicated investigations ...(bronchoscopy, BAL, blood tests, and induced sputum) were compared. The significant proportion of Lin- cells that did not express any of the currently accepted ILC2 surface markers therefore warrants further investigation. Because of a scarcity of reports of ILCs in human samples, we were unable to relate the proportion of Lin- CD127- cells in BAL and sputum from our patients to previous findings.
Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT ...cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation-driving cytokine release and Granzyme B upregulation-is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology.
Background TH 2 cytokines are not responsible for the ongoing symptoms and pathology in children with severe therapy-resistant asthma (STRA). IL-33 induces airway hyperresponsiveness, but its role in ...airway remodeling and steroid resistance is unknown. Objective We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA. Methods IL-33 levels were quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodeling and IL-33 levels was assessed. HDM-induced allergic airways disease (AAD) in neonatal ST2−/− mice lacking the IL-33 receptor was assessed, together with collagen production after IL-33 administration. The effect of steroid therapy on IL-33 levels in patients with neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsy (EB) specimens from children with STRA and related to remodeling, and collagen production by airway fibroblasts from pediatric patients stimulated with IL-33 and budesonide was quantified. Results Blocking IL-13 after AAD was established in neonatal mice and did not reduce remodeling or IL-33 levels; airway hyperresponsiveness was only partially reduced. IL-33 promoted collagen synthesis both from asthmatic fibroblasts from pediatric patients and after intranasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in EB specimens from children with STRA, whereas remodeling was absent in HDM-exposed ST2−/− mice. IL-33 levels were maintained, whereas IL-13 levels were abrogated by steroid treatment in neonatal HDM-exposed mice and in EB specimens from children with STRA. Conclusion IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.
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.
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•Epithelial-derived TGF-β drives pulmonary response to allergen•Epithelial TGF-β promotes GATA3-driven cytokine production by suppression of Sox4•TGF-β is chemoactive for innate lymphoid cells that express TGF-βRII•The local pulmonary environmental niche defines the nature of immune reactions
The role of epithelial-derived TGF-β in the pathogenesis of asthma is unknown. Lloyd and colleagues demonstrate that epithelial TGF-β is essential for the generation of the pulmonary allergic response to allergen by acting as a chemoactive factor for innate lymphoid type 2 cells and promoting GATA3-induced cytokine expression.
Abstract 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.
Idiopathic pulmonary fibrosis (IPF) is the most severe form of chronic lung fibrosis. Circulating monocytes have been implicated in immune pathology in IPF but their phenotype is unknown. In this ...work, we determined the immune phenotype of monocytes in IPF using multi-colour flow cytometry, RNA sequencing and corresponding serum factors, and mapped the main findings to amount of lung fibrosis and single cell transcriptomic landscape of myeloid cells in IPF lungs. We show that monocytes from IPF patients displayed increased expression of CD64 (FcγR1) which correlated with amount of lung fibrosis, and an amplified type I IFN response
. These were accompanied by markedly raised CSF-1 levels, IL-6, and CCL-2 in serum of IPF patients. Interrogation of single cell transcriptomic data from human IPF lungs revealed increased proportion of CD64
monocytes and "transitional macrophages" with higher expression of CCL-2 and type I IFN genes. Our study shows that monocytes in IPF patients are phenotypically distinct from age-matched controls, with a primed type I IFN pathway that may contribute to driving chronic inflammation and fibrosis. These findings strengthen the potential role of monocytes in the pathogenesis of IPF.
Abstract
Single cell spatial interrogation of the immune-structural interactions in COVID −19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted ...microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline Spatial Omics Oxford Pipeline (SpOOx) and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.
iNKT cells modulate severe influenza by reducing accumulation of inflammatory monocytes in lungs; possibly by targeting infected inflammatory monocytes for lysis.
Little is known of how a strong ...immune response in the lungs is regulated to minimize tissue injury during severe influenza A virus (IAV) infection. Here, using a model of lethal, high‐pathogenicity IAV infection, we first show that Ly6ChiLy6G– inflammatory monocytes, and not neutrophils, are the main infiltrate in lungs of WT mice. Mice devoid of iNKT cells (Jα18−/− mice) have increased levels of inflammatory monocytes, which correlated with increased lung injury and mortality (but not viral load). Activation of iNKT cells correlated with reduction of MCP‐1 levels and improved outcome. iNKT cells were able to selectively lyse infected, MCP‐1‐producing monocytes in vitro, in a CD1d‐dependent process. Our study provides a detailed profile and kinetics of innate immune cells in the lungs during severe IAV infection, highlighting inflammatory monocytes as the major infiltrate and identifying a role for iNKT cells in control of these cells and lung immune‐pathology.
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