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The Journal of Clinical Investigation Aug 2023Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies...
Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and nonspecific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that (a) PLSCR1 bound to and physically interacted with chemoattractant receptor-homologous molecule(CRTH2), which is a G-protein-coupled receptor that is expressed on TH2 cells and on multiple immune cells and is commonly used to identify ILC2 cells, and (b) the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2-dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.
Topics: Animals; Mice; Immunity, Innate; Phospholipid Transfer Proteins; Lymphocytes; Inflammation; Asthma; Lung; Cytokines
PubMed: 37289545
DOI: 10.1172/JCI169583 -
Nature Communications Aug 2023Biomaterial scaffolds mimicking the environment in metastatic organs can deconstruct complex signals and facilitate the study of cancer progression and metastasis. Here...
Biomaterial scaffolds mimicking the environment in metastatic organs can deconstruct complex signals and facilitate the study of cancer progression and metastasis. Here we report that a subcutaneous scaffold implant in mouse models of metastatic breast cancer in female mice recruits lung-tropic circulating tumor cells yet suppresses their growth through potent in situ antitumor immunity. In contrast, the lung, the endogenous metastatic organ for these models, develops lethal metastases in aggressive breast cancer, with less aggressive tumor models developing dormant lungs suppressing tumor growth. Our study reveals multifaceted roles of neutrophils in regulating metastasis. Breast cancer-educated neutrophils infiltrate the scaffold implants and lungs, secreting the same signal to attract lung-tropic circulating tumor cells. Second, antitumor and pro-tumor neutrophils are selectively recruited to the dormant scaffolds and lungs, respectively, responding to distinct groups of chemoattractants to establish activated or suppressive immune environments that direct different fates of cancer cells.
Topics: Female; Animals; Mice; Neutrophils; Lung Neoplasms; Neoplastic Cells, Circulating; Lung; Biocompatible Materials; Cell Line, Tumor; Neoplasm Metastasis; Tumor Microenvironment
PubMed: 37553342
DOI: 10.1038/s41467-023-40478-5 -
Cells Dec 2023Macrophages and monocytes orchestrate inflammatory processes in the lungs. However, their role in the pathogenesis of chronic obstructive pulmonary disease (COPD), an...
BACKGROUND
Macrophages and monocytes orchestrate inflammatory processes in the lungs. However, their role in the pathogenesis of chronic obstructive pulmonary disease (COPD), an inflammatory condition, is not well known. Here, we determined the characteristics of these cells in lungs of COPD patients and identified novel therapeutic targets.
METHODS
We analyzed the RNA sequencing (scRNA-seq) data of explanted human lung tissue from COPD (n = 18) and control (n = 28) lungs and found 16 transcriptionally distinct groups of macrophages and monocytes. We performed pathway and gene enrichment analyses to determine the characteristics of macrophages and monocytes from COPD (versus control) lungs and to identify the therapeutic targets, which were then validated using data from a randomized controlled trial of COPD patients (DISARM).
RESULTS
In the alveolar macrophages, 176 genes were differentially expressed (83 up- and 93 downregulated; P < 0.05, |logFC| > 0.5) and were enriched in downstream biological processes predicted to cause poor lipid uptake and impaired cell activation, movement, and angiogenesis in COPD versus control lungs. Classical monocytes from COPD lungs harbored a differential gene set predicted to cause the activation, mobilization, and recruitment of cells and a hyperinflammatory response to influenza. In silico, the corticosteroid fluticasone propionate was one of the top compounds predicted to modulate the abnormal transcriptional profiles of these cells. In vivo, a fluticasone-salmeterol combination significantly modulated the gene expression profiles of bronchoalveolar lavage cells of COPD patients ( < 0.05).
CONCLUSIONS
COPD lungs harbor transcriptionally distinct lung macrophages and monocytes, reflective of a dysfunctional and hyperinflammatory state. Inhaled corticosteroids and other compounds can modulate the transcriptomic profile of these cells in patients with COPD.
Topics: Humans; Adrenal Cortex Hormones; Lung; Macrophages; Macrophages, Alveolar; Monocytes; Non-Randomized Controlled Trials as Topic; Pulmonary Disease, Chronic Obstructive
PubMed: 38132091
DOI: 10.3390/cells12242771 -
Pediatric Radiology Apr 2024Pediatric lung infections continue to be a leading cause of pediatric morbidity and mortality. Although both pediatric and general radiologists are familiar with typical... (Review)
Review
Pediatric lung infections continue to be a leading cause of pediatric morbidity and mortality. Although both pediatric and general radiologists are familiar with typical lung infections and their imaging findings in children, relatively rare lung infections continue to present a diagnostic challenge. In addition, the advances in radiological imaging and emergence of several new lung infections in recent years facilitated the need for up-to-date knowledge on this topic. In this review article, we discuss the imaging findings of pediatric lung infections caused by unusual/uncommon and new pathogens. We review the epidemiological, clinical, and radiological imaging findings of viral (coronavirus disease 2019, Middle East respiratory syndrome, bird flu), bacterial (Streptococcus anginosus, Francisella tularensis, Chlamydia psittaci), and parasitic lung infections (echinococcosis, paragonimiasis, amoebiasis). Additional disorders whose clinical course and imaging findings may mimic lung infections in children (hypersensitivity pneumonitis, pulmonary hemorrhage, eosinophilic pneumonia) are also presented, to aid in differential diagnosis. As the clinical presentation of children with new and unusual lung infections is often non-specific, imaging evaluation plays an important role in initial detection, follow-up for disease progression, and assessment of potential complications.
Topics: Child; Humans; Lung; Pneumonia; COVID-19; Lung Diseases; Thorax
PubMed: 38097820
DOI: 10.1007/s00247-023-05818-z -
International Journal of Molecular... Mar 2024Pulmonary fibrosis results from the deposition and proliferation of extracellular matrix components in the lungs. Despite being an airway disorder, pulmonary fibrosis... (Review)
Review
Pulmonary fibrosis results from the deposition and proliferation of extracellular matrix components in the lungs. Despite being an airway disorder, pulmonary fibrosis also has notable effects on the pulmonary vasculature, with the development and severity of pulmonary hypertension tied closely to patient mortality. Furthermore, the anatomical proximity of blood vessels, the alveolar epithelium, lymphatic tissue, and airway spaces highlights the need to identify shared pathogenic mechanisms and pleiotropic signaling across various cell types. Sensory nerves and their transmitters have a variety of effects on the various cell types within the lungs; however, their effects on many cell types and functions during pulmonary fibrosis have not yet been investigated. This review highlights the importance of gaining a new understanding of sensory nerve function in the context of pulmonary fibrosis as a potential tool to limit airway and vascular dysfunction.
Topics: Humans; Pulmonary Fibrosis; Lung; Afferent Pathways; Hypertension, Pulmonary; Respiratory Mucosa
PubMed: 38542511
DOI: 10.3390/ijms25063538 -
American Journal of Physiology. Lung... May 2024Acute respiratory distress syndrome (ARDS) is a fatal pulmonary disorder characterized by severe hypoxia and inflammation. ARDS is commonly triggered by systemic and... (Review)
Review
Acute respiratory distress syndrome (ARDS) is a fatal pulmonary disorder characterized by severe hypoxia and inflammation. ARDS is commonly triggered by systemic and pulmonary infections, with bacteria and viruses. Notable pathogens include , , , coronaviruses, influenza viruses, and herpesviruses. COVID-19 ARDS represents the latest etiological phenotype of the disease. The pathogenesis of ARDS caused by bacteria and viruses exhibits variations in host immune responses and lung mesenchymal injury. We postulate that the systemic and pulmonary metabolomics profiles of ARDS induced by COVID-19 pathogens may exhibit distinctions compared with those induced by other infectious agents. This review aims to compare metabolic signatures in blood and lung specimens specifically within the context of ARDS. Both prevalent and phenotype-specific metabolomic signatures, including but not limited to glycolysis, ketone body production, lipid oxidation, and dysregulation of the kynurenine pathways, were thoroughly examined in this review. The distinctions in metabolic signatures between COVID-19 and non-COVID ARDS have the potential to reveal new biomarkers, elucidate pathogenic mechanisms, identify druggable targets, and facilitate differential diagnosis in the future.
Topics: Humans; COVID-19; Respiratory Distress Syndrome; SARS-CoV-2; Lung; Metabolome; Biomarkers; Metabolomics
PubMed: 38469648
DOI: 10.1152/ajplung.00266.2023 -
Nature Communications Jul 2023CD8 T cell tissue resident memory (T) cells are especially suited to control pathogen spread at mucosal sites. However, their maintenance in lung is short-lived....
CD8 T cell tissue resident memory (T) cells are especially suited to control pathogen spread at mucosal sites. However, their maintenance in lung is short-lived. TCR-dependent NFkB signaling is crucial for T cell memory but how and when NFkB signaling modulates tissue resident and circulating T cell memory during the immune response is unknown. Here, we find that enhancing NFkB signaling in T cells once memory to influenza is established, increases pro-survival Bcl-2 and CD122 levels thus boosting lung CD8 T maintenance. By contrast, enhancing NFkB signals during the contraction phase of the response leads to a defect in CD8 T differentiation without impairing recirculating memory subsets. Specifically, inducible activation of NFkB via constitutive active IKK2 or TNF interferes with TGFβ signaling, resulting in defects of lung CD8 T imprinting molecules CD69, CD103, Runx3 and Eomes. Conversely, inhibiting NFkB signals not only recovers but improves the transcriptional signature and generation of lung CD8 T. Thus, NFkB signaling is a critical regulator of tissue resident memory, whose levels can be tuned at specific times during infection to boost lung CD8 T.
Topics: Humans; Influenza, Human; Immunologic Memory; CD8-Positive T-Lymphocytes; Lung; Signal Transduction; NF-kappa B
PubMed: 37468506
DOI: 10.1038/s41467-023-40107-1 -
Short-range interactions between fibrocytes and CD8 T cells in COPD bronchial inflammatory response.ELife Jul 2023Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells....
Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells. Tissue fibrocytes interaction with CD8 T cells and its consequences were investigated using a combination of , experiments and mathematical modeling. We show that fibrocytes and CD8 T cells are found in the vicinity of distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8 T cells and fibrocytes are associated with altered lung function. Tissular CD8 T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8 T cells establish short-term interactions with fibrocytes, that trigger CD8 T cell proliferation in a CD54- and CD86-dependent manner, pro-inflammatory cytokines production, CD8 T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the model's ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8 T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8 T cells could jeopardize the balance between protective immunity and chronic inflammation in the bronchi of COPD patients.
Topics: Humans; CD8-Positive T-Lymphocytes; Pulmonary Disease, Chronic Obstructive; Bronchi; Epithelial Cells; Inflammation
PubMed: 37494277
DOI: 10.7554/eLife.85875 -
Journal of Thoracic Oncology : Official... Nov 2023Lung cancer remains the deadliest cancer in the world, and lung cancer survival is heavily dependent on tumor stage at the time of detection. Low-dose computed...
INTRODUCTION
Lung cancer remains the deadliest cancer in the world, and lung cancer survival is heavily dependent on tumor stage at the time of detection. Low-dose computed tomography screening can reduce mortality; however, annual screening is limited by low adherence in the United States of America and still not broadly implemented in Europe. As a result, less than 10% of lung cancers are detected through existing programs. Thus, there is a great need for additional screening tests, such as a blood test, that could be deployed in the primary care setting.
METHODS
We prospectively recruited 1384 individuals meeting the National Lung Screening Trial demographic eligibility criteria for lung cancer and collected stabilized whole blood to enable the pipetting-free collection of material, thus minimizing preanalytical noise. Ultra-deep small RNA sequencing (20 million reads per sample) was performed with the addition of a method to remove highly abundant erythroid RNAs, and thus open bandwidth for the detection of less abundant species originating from the plasma or the immune cellular compartment. We used 100 random data splits to train and evaluate an ensemble of logistic regression classifiers using small RNA expression of 943 individuals, discovered an 18-small RNA feature consensus signature (miLung), and validated this signature in an independent cohort (441 individuals). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin.
RESULTS
We generated diagnostic models and report a median receiver-operating characteristic area under the curve of 0.86 (95% confidence interval [CI]: 0.84-0.86) in the discovery cohort and generalized performance of 0.83 in the validation cohort. Diagnostic performance increased in a stage-dependent manner ranging from 0.73 (95% CI: 0.71-0.76) for stage I to 0.90 (95% CI: 0.89-0.90) for stage IV in the discovery cohort and from 0.76 to 0.86 in the validation cohort. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased after surgery with curative intent. In additional experiments, results of dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted through home sampling.
CONCLUSIONS
These data suggest the potential of a small RNA-based blood test as a viable alternative to low-dose computed tomography screening for early detection of smoking-associated lung cancer.
Topics: Humans; Lung Neoplasms; Early Detection of Cancer; Lung; Smoking; RNA
PubMed: 37437883
DOI: 10.1016/j.jtho.2023.07.005 -
Nature Communications Dec 2023Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure....
Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure causes significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s due to diminished production of microbiota-derived butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (Gpr41) or type 1 interferon receptor IFNAR1 (Ifnar1) recapitulate the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induces epigenetic changes in ILC2s and has a long-lasting deteriorative effect on allergic airway inflammation in adult offspring. Prenatal supplementation of butyrate ameliorates airway inflammation in adult mice born to antibiotic-exposed dams. These observations demonstrate an essential role for the microbiota in the control of type 2 innate immunity at the neonatal stage, which suggests a therapeutic window for treating asthma in early life.
Topics: Animals; Mice; Butyrates; Cytokines; Down-Regulation; Immunity, Innate; Inflammation; Lung; Lymphocytes; Anti-Bacterial Agents; Maternal Exposure; Interferon Type I
PubMed: 38097561
DOI: 10.1038/s41467-023-43903-x