Journal of Innate Immunity最新文献

Respiratory system diseases, including infections, inflammation, fibrosis, cancer, and others, impose a substantial burden on human health worldwide. The respiratory tract is constantly exposed to external stimuli due to its connection with the outside environment. Therefore, the immune system plays a crucial role in respiratory diseases. Toll-like receptors (TLRs) recognize pathogens and initiate immune responses, serving as the first line of host defense against external pathogen invasion. Interleukin-1 receptor-associated kinases (IRAKs) are a group of kinases that mediate activation signals from TLRs and the interleukin-1 receptor (IL-1R). Among the four distinct IRAK family members, interleukin-1 receptor-associated kinase M (IRAK-M) uniquely functions as a pseudokinase and serves as a critical negative regulator of TLR/IL-1R signaling pathways, mediating diverse immunomodulatory effects in various pulmonary diseases. This review focuses on recent advancements in understanding the role of IRAK-M in lung disorders, aiming to provide a basis for future investigations into the pathogenesis and potential therapeutic targets for such conditions.

Abnormal immune responses are common clinical features in septic patients. γδ T cells, as innate immune cells, play an important role in host defense, immune surveillance and homeostasis. However, the immune characteristics of γδ T cells in pediatric sepsis remains remain poorly understood. In this study, we analyzed single-cell RNA high-throughput sequencing data of peripheral blood mononuclear cells (PBMCs) from pediatric septic patients. It demonstrates that γδ T cells exhibit a proinflammatory state with heightened immune responsiveness to pathogens in pediatric sepsis, as confirmed by the results of flow cytometric analysis showing elevated Th1 cytokines secretion, increased activation, and a propensity to differentiate into IL-17-producing (γδT17) cells during disease progression. Pseudotime analysis identified seven key genes potentially regulating the differentiation of γδ T cells to γδT17 subtype. Furthermore, cell-cell communication analysis revealed enhanced RETN-CAP1 binding between neutrophils and γδ T cells in pediatric sepsis, suggesting that neutrophil-derived resistin may promote γδ T cell differentiation into the γδT17 subtype via CAP1 receptor binding. In conclusion, this study provides a single-cell study that analyzed the immune status of γδ T cells in pediatric sepsis, highlighting their pivotal roles in pathogen response, inflammation propagation, and immune regulation. The observed differentiation toward the γδT17 subtype may facilitate neutrophil recruitment in this life-threatening condition. Elucidating the molecular mechanisms of γδ T cells in pediatric sepsis could offer a new theoretical basis for novel therapeutics.

Piezo-type mechanosensitive ion channel component 1 (Piezo1) is an evolutionarily conserved and multifunctional mechanosensitive ion channel protein that has emerged as a significant contributor to the pathogenesis of inflammatory bowel disease (IBD). Piezo1 plays a crucial role in regulating intestinal barrier integrity, immune responses, and the intestinal nervous system, thereby influencing disease progression. Its expression patterns correlate with disease severity and inflammatory markers in IBD patients, indicating its potential as a diagnostic and prognostic biomarker. Mechanistically, Piezo1 activation modulates key signaling pathways involved in IBD, including NF-κB, ROCK, mTOR, and 5-HT signaling pathways. Targeting Piezo1, either by modulating its expression or function, represents a promising therapeutic strategy for IBD. This review summarizes the current understanding of Piezo1's structure, biological functions, mechanisms of action, and clinical implications in the context of IBD, providing insights into its potential as a therapeutic target and biomarker for this chronic gastrointestinal disorder.

Interstitial lung diseases (ILDs), or diffuse parenchymal lung diseases, are general terms for a group of over 200 conditions that result from the destruction of cells neighbouring the alveoli, leading to extensive inflammation and fibrosis of the lungs. Although different types of ILD have distinct pathophysiology, clinical display and advancement, many forms drive irreversible pulmonary fibrosis (PF), leading to progressive functional impairment, respiratory failure, and mortality. Key components of innate immunity include proteases and their cognate inhibitors, which are involved in respiratory homeostasis. Alterations to the protease-antiprotease balance can lead to pulmonary disease and fibrotic scarring of the lungs, and over the past two decades, there has been a surge in research exploring their effect on the pathogenesis of ILDs. We have evaluated relevant studies regarding these enzymes in the context of lung fibrosis and have discussed prospects for developing novel treatments. This review will place greater emphasis on the overall effect of proteases and antiproteases to the development of PF as studied using both in vivo and in vitro models. Considering the limited therapeutic interventions, continued research on proteolytic enzymes and their inhibitors is required for the development of novel, effective treatments for PF.

Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling and epithelial cell dysfunction, yet the underlying regulatory mechanisms remain incompletely understood. This study aimed to investigate the role of ATP synthase subunit β (ATP5B) in COPD pathogenesis, with a focus on epithelial heterogeneity and airway remodeling. We employed single-cell RNA sequencing (scRNA-seq) to analyze small airway epithelial cells and identify key cell populations and hub genes. ATP5B was identified through the intersection of differentially expressed genes (DEGs) and epithelial markers. In vitro experiments were conducted using 2% (volume/volume, v/v) cigarette smoke extract (CSE)-treated BEAS-2B cells, and in vivo validation was performed in CS/LPS-induced COPD mouse models. scRNA-seq identified 12 distinct epithelial clusters, with ATP5B emerging as a central hub gene. ATP5B expression was significantly upregulated in CSE-treated BEAS-2B cells (fold change = 1.92, p < 0.05). ATP5B knockdown reversed CSE-induced apoptosis (fold change = 0.397, p < 0.05), reduced inflammatory cytokines (e.g., IL-6: 0.40; TNF-α: 0.46, p < 0.05), and suppressed EMT marker expression (E-cadherin↑, Vimentin↓). In vivo, ATP5B silencing alleviated airway remodeling and inflammation. Mechanistically, GSEA and experimental validation demonstrated that ATP5B activates the Toll-like receptor (TLR) signaling pathway to promote airway remodeling. Our findings reveal ATP5B as a key regulator of airway remodeling in COPD via TLR signaling activation, suggesting its potential as a diagnostic biomarker and therapeutic target.

Introduction: Post-Sepsis Syndrome (PSS) is marked by persistent immune dysregulation, leading to long-term complications that overlap with autoimmune responses. Uncovering key immune-related candidate genes during PSS recovery can enhance our understanding of immune mechanisms involved in post-sepsis complications and inform targeted therapeutic strategies.

Methods: Analyze the GSE46955 dataset containing 24 peripheral blood mononuclear cell (PBMC) samples: 8 from the sepsis stage, 8 from the recovery phase, and 6 from healthy controls. Use the Linear Models for Microarray Data (limma) and Weighted Gene Co-expression Network Analysis (WGCNA) to identify differentially expressed genes (DEGs). Further explore key genes and pathways in sepsis recovery through protein-protein interaction (PPI) networks, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and a lipopolysaccharide (LPS)-induced mouse model.

Results: A total of 537 DEGs were identified, showing significant expression differences between sepsis and healthy controls. CD4, C1QA, and HLA-DRA were key hub genes in the PPI network, with increased expression in recovery samples, indicating roles in immune regulation. CD4 silencing worsened sepsis and reduced survival in mice, while CD4 overexpression improved outcomes.

Conclusion: Our findings highlight immune candidate genes that could serve as diagnostic and therapeutic targets in PSS, shedding light on the prolonged immune responses underlying sepsis recovery. These insights support the development of interventions targeting immune dysregulation in PSS, potentially applicable to other autoimmune conditions.

Introduction: The complement system plays a crucial role in bridging innate and adaptive immune responses. When activated, a proteolytic cascade leads to pathogen destruction. It is initiated via the recognition of foreign structures by three pathways: the classical, the lectin, and the alternative. This study focuses on the lectin pathway and the role of four pattern recognition molecules (PRMs), mannan-binding lectin, H-ficolin, L-ficolin, and M-ficolin, in the recognition of microbial patterns and the initiation of complement activation. These PRMs bind to specific carbohydrate structures; each PRM has unique ligand specificities. We investigated the PRM interactions with lipopolysaccharide (LPS) of Gram-negative bacteria.

Methods: Utilizing a microarray of 120 distinct LPS structures, the study aims to map the diversity of PRM-LPS interactions and assess their role in complement activation.

Results: Our findings reveal that all four PRMs preferentially bind to the O-antigens of LPS, rather than lipid A or the core oligosaccharide, contradicting previous suggestions. Each PRM displayed distinct binding patterns to different LPS structures, although some overlaps were observed. These interactions were partially confirmed with whole bacteria. MBL binding to E. coli O30 and O126, as well as H-ficolin binding to E. coli O108 led to complement activation on the bacterial surface.

Conclusion: The application of a wide array of LPS structures expands and clarifies the spectrum of bacterial glycoconjugates that interact with PRMs, known to activate the complement system.