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BACKGROUND: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes. OBJECTIVE: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs). METHODS: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps. RESULTS: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo. CONCLUSION: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches.
Assuntos
Asma , Biomarcadores , Vesículas Extracelulares , Galectinas , Sinusite , Humanos , Asma/sangue , Asma/fisiopatologia , Asma/imunologia , Asma/diagnóstico , Vesículas Extracelulares/metabolismo , Feminino , Masculino , Galectinas/sangue , Biomarcadores/sangue , Adulto , Pessoa de Meia-Idade , Sinusite/sangue , Sinusite/imunologia , Rinite/sangue , Rinite/imunologia , Rinite/fisiopatologia , Pólipos Nasais/imunologia , Pólipos Nasais/sangue , Eosinófilos/imunologia , Idoso , Doença CrônicaRESUMO
Since the advent of single-cell RNA sequencing (scRNA-seq) methodology, single-cell analysis has become a powerful tool for exploration of cellular networks and dysregulated immune responses in disease pathogenesis. Advanced bioinformatics tools have enabled the combined analysis of scRNA-seq data and information on various cell properties, such as cell surface molecular profiles, chromatin accessibility and spatial information, leading to a deeper understanding of pathology. This Review provides an overview of the achievements in single-cell analysis applied to clinical samples of rheumatic and allergic diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, allergic airway diseases and atopic dermatitis, with an expanded scope beyond peripheral blood cells to include local diseased tissues. Despite the valuable insights that single-cell analysis has provided into disease pathogenesis, challenges remain in translating single-cell findings into clinical practice and developing personalized treatment strategies. Beyond understanding the atlas of cellular diversity, we discuss the application of data obtained in each study to clinical practice, with a focus on identifying biomarkers and therapeutic targets.
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Regulated neural-metabolic-inflammatory responses are essential for maintaining physiological homeostasis. However, the molecular machinery that coordinates neural, metabolic, and inflammatory responses is largely unknown. Here, we show that semaphorin 6D (SEMA6D) coordinates anxiogenic, metabolic, and inflammatory outputs from the amygdala by maintaining synaptic homeostasis. Using genome-wide approaches, we identify SEMA6D as a pleiotropic gene for both psychiatric and metabolic traits in human. Sema6d deficiency increases anxiety in mice. When fed a high-fat diet, Sema6d-/- mice display attenuated obesity and enhanced myelopoiesis compared with control mice due to higher sympathetic activity via the ß3-adrenergic receptor. Genetic manipulation and spatial and single-nucleus transcriptomics reveal that SEMA6D in amygdalar interneurons is responsible for regulating anxiogenic and autonomic responses. Mechanistically, SEMA6D is required for synaptic maturation and γ-aminobutyric acid transmission. These results demonstrate that SEMA6D is important for the normal functioning of the neural circuits in the amygdala, coupling emotional, metabolic, and inflammatory responses.
RESUMO
Immune checkpoint inhibitors (ICIs) are indicated for a diverse range of cancer types, and characterizing the tumor immune microenvironment is critical for optimizing therapeutic strategies, including ICIs. T cell infiltration and activation status in the tumor microenvironment greatly affects the efficacy of ICIs. Here, we show that semaphorin 6D (Sema6D) forward signaling, which is reportedly involved in coordinating the orientation of cell development and migration as a guidance factor, impaired the infiltration and activation of tumor-specific CD8+ T cells in murine oral tumors. Sema6D expressed by nonhematopoietic cells was responsible for this phenotype. Plexin-A4, a receptor for Sema6D, inhibited T cell infiltration and partially suppressed CD8+ T cell activation and proliferation induced by Sema6D stimulation. Moreover, mouse oral tumors, which are resistant to PD-1-blocking treatment in wild-type mice, showed a response to the treatment in Sema6d-KO mice. Finally, analyses of public data sets of human head and neck squamous cell carcinoma, pan-cancer cohorts, and a retrospective cohort study showed that SEMA6D was mainly expressed by nonhematopoietic cells such as cancer cells, and SEMA6D expression was significantly negatively correlated with CD8A, PDCD1, IFNG, and GZMB expression. Thus, targeting Sema6D forward signaling is a promising option for increasing ICI efficacy.