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The ubiquitous Torque teno virus (TTV) establishes a chronically persistent infection in the human host. TTV has not been associated with any apparent disease, but, as part of the human virome, it may confer a regulatory imprint on the human immune system with as yet unclear consequences. However, so far, only few studies have characterized the TTV-specific immune responses or the overall immunological imprints by TTV. Here, we reveal that TTV infection leads to a highly exhausted TTV-specific CD8+ T-cell response, hallmarked by decreased IFN-g production and the expression of the inhibitory NKG2Areceptor. On a functional level, we identified a panel of highly polymorphic TTV-encoded peptides that lead to an expansion of regulatory NKG2A+ natural killer, NKG2A+CD4+, and NKG2A+CD8+ T cells via the stabilization of the nonclassical HLA-E molecule. Our results thus demonstrate that TTV leads to a distinct imprint on the human immune system that may further regulate overall human immune responses in infectious, autoimmune, and malignant diseases. [ABSTRACT FROM AUTHOR]

SAPHO syndrome is a complex inflammatory disorder affecting the skin and bones, characterized by osteomyelitis, acne, and pustulosis. Cytokines play a pivotal role in the pathogenesis of SAPHO syndrome, especially in inflammatory responses and immune regulation. This article reviews the cytokines involved in the pathogenesis of SAPHO syndrome, such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, IL-10, and transforming growth factor-β (TGF-β), and discusses their potential as intervention points for treatment. These findings elucidate the intricate immune regulatory network of SAPHO syndrome and provide a theoretical foundation for the development of new targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Melatonin (N-acetyl-5-methoxytryptamine) is an essential small molecule with diverse biological functions. It plays several key roles, including regulating the secretion of reproductive hormones and the reproductive cycle, enhancing the functionality of reproductive organs, improving the quality of sperm and eggs, and mitigating oxidative stress in the reproductive system. Melatonin effectively inhibits and scavenges excess free radicals while activating the antioxidant enzyme system and reduces the production of inflammatory factors and alleviates tissue damage caused by inflammation by regulating inflammatory pathways. Additionally, melatonin contributes to repairing the intestinal barrier and regulating the gut microbiota, thereby reducing bacterial and toxin permeation. The use of melatonin as an endogenous hormone in animal husbandry has garnered considerable attention because of its positive effects on animal production performance, reproductive outcomes, stress adaptation, disease treatment, and environmental sustainability. This review explores the characteristics and biological functions of melatonin, along with its current applications in animal production. Our findings may serve as a reference for the use of melatonin in animal farming and future developmental directions. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic skin disease with an increasing prevalence each year. However, the mechanisms underlying its onset and progression remain unclear, and effective therapeutic targets are lacking. Therefore, we employs an innovative approach by combining single‐cell RNA sequencing (scRNA‐seq) with meta‐analysis. This not only elucidates the potential mechanisms of psoriasis at the cellular level but also identifies immunoregulatory marker genes that play a statistically significant role in driving psoriasis progression through comprehensive analysis of multiple datasets. Skin tissue samples from 12 psoriasis patients underwent scRNA‐seq, followed by quality control, filtering, PCA dimensionality reduction, and tSNE clustering analysis to identify T cell subtypes and differentially expressed genes (DEGs) in psoriatic skin tissue. Next, three psoriasis datasets were standardised and merged to identify differentially expressed genes (DEGs). Subsequently, weighted gene co‐expression network analysis (WGCNA) was applied for clustering analysis of gene co‐expression network modules and to assess the correlation between these modules and DEGs. Least absolute shrinkage and selection operator (LASSO) regression and receiver operating characteristic (ROC) curve analyses were conducted to select disease‐specific genes and evaluate their diagnostic value. Single‐cell data revealed nine cell types in psoriatic skin tissue, with seven T cell subtypes identified. Intersection analysis identified ADAM8 and G3BP2 as key genes. Through the integration of scRNA‐seq and Meta analysis, we identified the immunoregulatory marker gene G3BP2, which is associated with the onset and progression of psoriasis and holds clinical significance. G3BP2 is speculated to promote the development of psoriasis by increasing the proportion of CD8+ T cells. [ABSTRACT FROM AUTHOR]

Introduction: Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. Method: In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. Results: A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Discussion: Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication. [ABSTRACT FROM AUTHOR]

Following transplantation, human CD4+T cells can respond to alloantigen using three distinct pathways. Direct and semi-direct responses are considered potent, but brief, so contribute mostly to acute rejection. Indirect responses are persistent and prolonged, involve B cells as critical antigen presenting cells, and are an absolute requirement for development of donor specific antibody, so more often mediate chronic rejection. Novel in vitro techniques have furthered our understanding by mimicking in vivo germinal centre processes, including B cell antigen presentation to CD4+ T cells and effector cytokine responses following challenge with donor specific peptides. In this review we outline recent data detailing the contribution of CD4+ T follicular helper cells and antigen presenting B cells to donor specific antibody formation and antibody mediated rejection. Furthermore, multi-parametric flow cytometry analyses have revealed specific endogenous regulatory T and B subsets each capable of suppressing distinct aspects of the indirect response, including CD4+ T cell cytokine production, B cell maturation into plasmablasts and antibody production, and germinal centre maturation. These data underpin novel opportunities to control these aberrant processes either by targeting molecules critical to indirect alloresponses or potentiating suppression via exogenous regulatory cell therapy. [ABSTRACT FROM AUTHOR]

SET domain‐containing 2 (SETD2) is a histone methyltransferase. It regulates the activity of H3K36me3 to enhance gene transcription. Macrophages (Mϕs) are one of the cell types involved in immune response. The purpose of this study is to clarify the role of SETD2 in regulating the immune property of Mϕ. The Mφs were isolated from the bronchoalveolar lavage fluid (BALF) and analysed through flow cytometry and RNA sequencing. A mouse strain carrying Mφs deficient in SETD2 was used. A mouse model of airway allergy was established with the ovalbumin/alum protocol. Less expression of SETD2 was observed in airway Mϕs in patients with allergic asthma. SETD2 of M2 cells was associated with the asthmatic clinical response. Sensitization reduced the expression of SETD2 in mouse respiratory tract M2 cells, which is associated with the allergic reaction. Depletion of SETD2 in Mφs resulted in Th2 pattern inflammation in the lungs. SETD2 maintained the immune regulatory ability in airway M2 cells. SETD2 plays an important role in the maintenance of immune regulatory property of airway Mφs. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a versatile environmental sensor and transcription factor found throughout the body, responding to a wide range of small molecules originating from the environment, our diets, host microbiomes, and internal metabolic processes. Increasing evidence highlights AhR's role as a critical regulator of numerous biological functions, such as cellular differentiation, immune response, metabolism, and even tumor formation. Typically located in the cytoplasm, AhR moves to the nucleus upon activation by an agonist where it partners with either the aryl hydrocarbon receptor nuclear translocator (ARNT) or hypoxia-inducible factor 1β (HIF-1β). This complex then interacts with xenobiotic response elements (XREs) to control the expression of key genes. AhR is notably present in various crucial immune cells, and recent research underscores its significant impact on both innate and adaptive immunity. This review delves into the latest insights on AhR's structure, activating ligands, and its multifaceted roles. We explore the sophisticated molecular pathways through which AhR influences immune and lymphoid cells, emphasizing its emerging importance in managing inflammatory diseases. Furthermore, we discuss the exciting potential of developing targeted therapies that modulate AhR activity, opening new avenues for medical intervention in immune-related conditions. [ABSTRACT FROM AUTHOR]

Background: Periodontal tissue loss is the main reason for tooth mobility and loss caused by periodontal disease. Dental follicle stem cells (DFSCs) have significant therapeutic potential in periodontal regeneration, which maybe mainly depends on their potent immunomodulatory capacity. Consequently, this study aims to elucidate the impact of implanted xenogenous DFSCs on innate immune responses during early and late stages in the periodontal defect repair period. Methods: To trace and investigate the immunomodulation mechanisms of DFSCs in vivo, DFSCs were engineered (E-DFSCs) using lentiviral vectors expressing CD63-enhanced green fluorescent protein (CD63-EGFP) and β-Actin-mCherry protein (ACTB-mCherry) to exhibit green and red fluorescence. The biological characteristics and functions of E-DFSCs were verified by proliferation, differentiation, and co-culture experiments in vitro. In vivo, the periodontal regeneration capacity of E-DFSCs was detected by implantation of murine periodontal defect model, and the response of innate immune cells was detected at the 1st, 3rd, and 5th days (early stage) and 4th week (late stage) after implantation. Results: In vitro assessments showed that E-DFSCs retain similar properties to their non-engineered counterparts but exhibit enhanced macrophage immunomodulation capability. In mice models, four-week micro-CT and histological evaluations indicated that E-DFSCs have equivalent efficiency to DFSCs in periodontal defect regeneration. At the early stage of repair in mice periodontal defect, fluorescence tracking showed that implanted E-DFSCs might primarily activate endogenous cells through direct contact and indirect actions, and most of these cells are myeloperoxidase-positive neutrophils. Additionally, compared with the control group, the neutrophilic infiltration and conversion of N2-type were significantly increased in the E-DFSC group. At the late stage of defect regeneration, more M2-type macrophages, fewer TRAP + osteoclasts, and an upregulated OPG/RANKL ratio were detected in the E-DFSC group compared to the control group, which indicated that immune balance tilts towards healing and bone formation. Conclusion: The xenogenous implanted DFSCs can induce the N2 phenotype of neutrophils in the early stage, which can activate the innate immune mechanism of the host to promote periodontal tissue regeneration. [ABSTRACT FROM AUTHOR]

Degenerative spinal stenosis is a chronic disease that affects the spinal ligaments and associated bones, resulting in back pain and disorders of the limbs among the elderly population. There are few preventive strategies for such ligament degeneration. We here aimed to establish a comprehensive transcriptomic atlas of ligament tissues to identify high‐priority targets for pharmaceutical treatment of ligament degeneration. Here, single‐cell RNA sequencing was performed on six degenerative ligaments and three traumatic ligaments to understand tissue heterogeneity. After stringent quality control, high‐quality data were obtained from 32,014 cells. Distinct cell clusters comprising stromal and immune cells were identified in ligament tissues. Among them, we noted that collagen degradation associated with CTHRC1+ fibroblast‐like cells and calcification linked to CRTAC1+ chondrocyte‐like cells were key features of ligament degeneration. SCENIC analysis and further experiments identified ATF3 as a key transcription factor regulating the pathogenesis of CRTAC1+ chondrocyte‐like cells. Typically, immune cells infiltrate localized organs, causing tissue damage. In our study, myeloid cells were found to be inflammatory‐activated, and SPP1+ macrophages were notably enriched in degenerative ligaments. Further exploration via CellChat analysis demonstrated a robust interaction between SPP1+ macrophages and CRTAC1+ chondrocyte‐like cells. Activated by SPP1, ATF3 propels the CRTAC1/MGP/CLU axis, fostering ligament calcification. Our unique resource provides novel insights into possible mechanisms underlying ligament degeneration, the target cell types, and molecules that are expected to mitigate degenerative spinal ligament. We also highlight the role of immune regulation in ligament degeneration and calcification, enhancing our understanding of this disease. [ABSTRACT FROM AUTHOR]

Limbal mesenchymal stromal cells (LMSCs) reside in the limbal niche, supporting corneal integrity and facilitating regeneration. While mesenchymal stem/stromal cells (MSCs) are used in regenerative therapies, there is limited knowledge about LMSC subpopulations and their characteristics. This study characterized human LMSC subpopulations through the flow cytometric assessment of fifteen cell surface markers, including MSC, wound healing, immune regulation, ASC, endothelial, and differentiation markers. Primary LMSCs were established from remnant human corneal transplant specimens and passaged eight times to observe changes during subculture. The results showed the consistent expression of typical MSC markers and distinct subpopulations with the passage-dependent expression of wound healing, immune regulation, and differentiation markers. High CD166 and CD248 expressions indicated a crucial role in ocular surface repair. CD29 expression suggested an immunoregulatory role. Comparable pigment-epithelial-derived factor (PEDF) expression supported anti-inflammatory and anti-angiogenic roles. Sustained CD201 expression indicated maintained differentiation capability, while VEGFR2 expression suggested potential endothelial differentiation. LMSCs showed higher VEGF expression than fibroblasts and endothelial cells, suggesting a potential contribution to ocular surface regeneration through the modulation of angiogenesis and inflammation. These findings highlight the heterogeneity and multipotent potential of LMSC subpopulations during in vitro expansion, informing the development of standardized protocols for regenerative therapies and improving treatments for ocular surface disorders. [ABSTRACT FROM AUTHOR]

Early innate immune responses play an important role in determining the protective outcome of Mycobacterium tuberculosis (Mtb) infection. Nuclear factor κB (NF-κB) signaling in immune cells regulates the expression of key downstream effector molecules that mount early antimycobacterial responses. Using conditional knockout mice, we studied the effect of abrogation of NF-κB signaling in different myeloid cell types and its impact on Mtb infection. Our results show that the absence of IKK2-mediated signaling in all myeloid cells resulted in increased susceptibility to Mtb infection. In contrast, the absence of IKK2-mediated signaling in CD11c+ myeloid cells induced early proinflammatory cytokine responses, enhanced the recruitment of myeloid cells, and mediated early resistance to Mtb. Abrogation of IKK2 in MRP8-expressing neutrophils did not affect disease pathology or Mtb control. Thus, we describe an early immunoregulatory role for NF-κB signaling in CD11c-expressing phagocytes and a later protective role for NF-κB in LysM-expressing cells during Mtb infection. [ABSTRACT FROM AUTHOR]

Myelodysplastic neoplasms (MDS) are clonal disorders of the myeloid lineage leading to peripheral blood cytopenias. Dysregulation of innate immunity is hypothesized to be a potent driver of MDS. A recent study revealed increased thrombomodulin (TM) expression on classical monocytes in MDS, which was associated with prolonged survival. TM is a receptor with immunoregulatory capacities, however, its exact role in MDS development remains to be elucidated. In this review we focus on normal monocyte biology and report on the involvement of monocytes in myeloid disease entities with a special focus on MDS. Furthermore, we delve into the current knowledge on TM and its function in monocytes in health and disease and explore the role of TM-expressing monocytes as driver, supporter or epiphenomenon in the MDS bone marrow environment. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative joint disease caused by chronic inflammation that damages articular cartilage. At present, the treatment of OA includes drug therapy to relieve symptoms and joint replacement therapy for advanced OA. However, these palliatives cannot truly block the progression of the disease from the immunological pathogenesis of OA. In recent years, bone marrow mesenchymal stem cell (BMSC) transplantation has shown great potential in tissue engineering repair. In addition, many studies have shown that BMSC paracrine signals play an important role in the treatment of OA through immune regulation and suppressing inflammation. At present, the mechanism of inflammation-induced OA and the use of BMSC transplantation in joint repair have been reviewed, but the mechanism and significance of BMSC paracrine signals in the treatment of OA have not been fully reviewed. Therefore, this article focused on the latest research progress on the paracrine effects of BMSCs in the treatment of OA and the related mechanisms by which BMSCs secrete cytokines to inhibit the inflammatory response, regulate immune balance, and promote cell proliferation and differentiation. In addition, the application potential of BMSCExos as a new type of cell-free therapy for OA is described. This review aimed to provide systematic theoretical support for the clinical application of BMSC transplantation in the treatment of OA. [ABSTRACT FROM AUTHOR]

Lithium is one of the lightest elements on Earth and it has been in the environment since the formation of the galaxy. While a common element, it has not been found to be an essential element in biological processes, ranging from single cell organisms to Homo sapiens. Instead, at an early stage of evolution, organisms committed to a range of elements such as sodium, potassium, calcium, magnesium, zinc, and iron to serve essential functions. Such ions serve critical functions in ion channels, as co-factors in enzymes, as a cofactor in oxygen transport, in DNA replication, as a storage molecule in bone and liver, and in a variety of other roles in biological processes. While seemingly excluded from a major essential role in such processes, lithium ions appear to be able to modulate a variety of biological processes and "correct" deviation from normal activity, as a deficiency of lithium can have biological consequences. Lithium salts are found in low levels in many foods and water supplies, but the effectiveness of Li salts to affect biological systems came to recent prominence with the work of Cade, who reported that administrating Li salts calmed guinea pigs and was subsequently effective at relatively high doses to "normalize" a subset of patients with bipolar disorders. Because of its ability to modulate many biological pathways and processes (e.g., cyclic AMP, GSK-3beta, inositol metabolism, NaK ATPases, neuro processes and centers, immune-related events, respectively) both in vitro and in vivo and during development and adult life, Li salts have become both a useful tool to better understand the molecular regulation of such processes and to also provide insights into altered biological processes in vivo during aging and in disease states. While the range of targets for lithium action supports its possible role as a modulator of biological dysregulation, it presents a conundrum for researchers attempting to elucidate its specific primary target in different tissues in vivo. This review will discuss aspects of the state of knowledge regarding some of the systems that can be influenced, focusing on those involving neural and autoimmunity as examples, some of the mechanisms involved, examples of how Li salts can be used to study model systems, as well as suggesting areas where the use of Li salts could lead to additional insights into both disease mechanisms and natural processes at the molecular and cell levels. In addition, caveats regarding lithium doses used, the strengths and weaknesses of rodent models, the background genetics of the strain of mice or rats employed, and the sex of the animals or the cells used, are discussed. Low-dose lithium may have excellent potential, alone or in combination with other interventions to prevent or alleviate aging-associated conditions and disease progression. [ABSTRACT FROM AUTHOR]

Wound healing progresses through three distinct stages: inflammation, proliferation, and remodeling. Immune regulation is a central component throughout, crucial for orchestrating inflammatory responses, facilitating tissue repair, and restraining scar tissue formation. Elements such as mitochondria, reactive oxygen species (ROS), macrophages, autophagy, ferroptosis, and cytokines collaboratively shape immune regulation in this healing process. Skin wound dressings, recognized for their ability to augment biomaterials' immunomodulatory characteristics via antimicrobial, antioxidative, pro- or anti-inflammatory, and tissue-regenerative capacities, have garnered heightened attention. Notwithstanding, a lack of comprehensive research addressing how these dressings attain immunomodulatory properties and the mechanisms thereof persists. Hence, this paper pioneers a systematic review of biomaterials, emphasizing immune regulation and their underlying immunological mechanisms. It begins by highlighting the importance of immune regulation in wound healing and the peculiarities and obstacles faced in skin injury recovery. This segment explores the impact of wound metabolism, infections, systemic illnesses, and local immobilization on the immune response during healing. Subsequently, the review examines a spectrum of biomaterials utilized in skin wound therapy, including hydrogels, aerogels, electrospun nanofiber membranes, collagen scaffolds, microneedles, sponges, and 3D-printed constructs. It elaborates on the immunomodulatory approaches employed by these materials, focusing on mitochondrial and ROS modulation, autophagic processes, ferroptosis, macrophage modulation, and the influence of cytokines on wound healing. Acknowledging the challenge of antibiotic resistance, the paper also summarizes promising plant-based alternatives for biomaterial integration, including curcumin. In its concluding sections, the review charts recent advancements and prospects in biomaterials that accelerate skin wound healing via immune modulation. This includes exploring mitochondrial transplantation materials, biomaterial morphology optimization, metal ion incorporation, electrostimulation-enabled immune response control, and the benefits of composite materials in immune-regulatory wound dressings. The ultimate objective is to establish a theoretical foundation and guide future investigations in the realm of skin wound healing and related materials science disciplines. [ABSTRACT FROM AUTHOR]

The triadic interplay between sleep, immunity, and cancer represents a growing area of biomedical research with significant clinical implications. This review synthesizes the current knowledge on how sleep influences immune function, the immune system's role in cancer dynamics, and the direct connections between sleep patterns and cancer risk. After a comprehensive overview of the interrelationships among these three domains, the mechanisms of sleep in immune function are described, detailing how sleep regulates the immune system, the effects of sleep duration and quality on immune responses, and the underlying molecular and cellular mechanisms. Also, the complex relationship between immunity and cancer is explored, highlighting the immune system's role in cancer prevention and progression, immune surveillance, tumor microenvironment, and the implications of immunodeficiency and immune modulation on cancer risk. The direct connections between sleep and cancer are then described, presenting epidemiological evidence linking sleep patterns to cancer risk, biological mechanisms that influence cancer development, and the role of sleep disorders in cancer prognosis. The mediating role of sleep between immunity and cancer is highlighted, proposing hypothesized pathways, summarizing evidence from experimental and clinical studies, and evaluating the impact of sleep interventions on immune function and cancer outcomes. This review concludes by discussing the clinical implications and future directions, emphasizing the potential for sleep-based interventions in cancer prevention and treatment, the integration of sleep management in oncology and immunotherapy, and outlining a future research agenda. This agenda includes understanding the mechanisms of the sleep–immunity–cancer interplay, conducting epidemiological studies on sleep and cancer risk, assessing the impact of sleep management in cancer treatment protocols, exploring sleep and tumor microenvironment interactions, and considering policy and public health implications. Through a detailed examination of these interconnected pathways, this review underscores the critical importance of sleep in modulating immune function and cancer outcomes, advocating for interdisciplinary research and clinical strategies to harness this knowledge for improved health outcomes. [ABSTRACT FROM AUTHOR]

Allergic asthma is characterized by the polarization of Th2 cells and impaired immune regulation. Macrophages occupy the largest proportion of airway immune cells. This study aims to discover the mechanism that hinders the immune regulatory functions of airway macrophages. In this study, macrophages were isolated from cells in bronchoalveolar lavage fluids (BALF) collected from asthma patients and normal control (NC) subjects. The results indicated that macrophages occupied the largest portion of the cellular components in BALF. The frequency of IL‐10+ macrophage was significantly lower in asthma patients than in NC subjects. The expression of IL‐10 in macrophages of BALF was associated with the levels of asthma‐related parameters. The immune‐suppressive functions of BALF M0 cells were defective in asthma patients. The inducibility of IL‐10 expression was impaired in BALF macrophages of asthma patients, which could be restored by exposing to CpG. In conclusion, the induction of IL‐10 in macrophages of BALF in asthma patients was impaired, and it could be restored by exposure to CpG. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. Methods: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. Results: A functional assay identified that transforming growth factor-β1 (TGF-β1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. Conclusions: These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD. [ABSTRACT FROM AUTHOR]

Background: Excessive inflammation is a major cause of implant failure. The surface morphology, hydrophilicity, and loading of biomaterials are major properties modulating anti-inflammatory macrophage activation. This paper investigates the regulatory effects of modifying the surface of Titanium dioxide nanotubes (TNTs) with graphene oxide (GO) on the polarization of mouse monocyte macrophages (RAW264.7). Methods: TNT was produced by the anodic oxidation of titanium. GO was subsequently electrodeposited on the TNT to obtain a TNT–GO composite. The samples were characterised through scanning electron microscopy (SEM), Raman spectroscopy, and X-ray diffraction. RAW264.7 cells were separately seeded onto the surface of three groups of samples: pure Ti, TNT, and TNT–GO. Under the condition of lipopolysaccharide stimulation, the influence of the sample surfaces on the gene expression profiles was investigated through RNA sequence analysis. In addition, cell spreading was observed through SEM, cell adhesion and proliferation were analysed using the CCK8 assay, and the expression of inflammation-related factors was investigated by ELISA and cellular immunofluorescence staining. The production of reactive oxygen species (ROS) in the RAW264.7 cells on the surface of the three groups was detected via immunofluorescence staining. Results: The CCK8 results indicated that the adhesion and proliferation of the RAW264.7 cells were reduced on the TNT and TNT–GO surfaces. ELISA results revealed significant differences in the pro-inflammatory factors tumour necrosis factor-α and interleukin-6 secretion among the three groups at 24 h (p < 0.05). The secretion of pro-inflammatory factors significantly reduced and the expression of anti-inflammatory factor IL-10 increased on the TNT and TNT–GO surfaces. The RNA sequencing, ELISA, and cell immunofluorescence staining test results suggested that the inflammatory response of M1 polarization was reduced and the M2 polarization of macrophages was induced on the TNT–GO surface, which may be attributed to the reduction in ROS production. Conclusions: Under lipopolysaccharide stimulation, the inflammatory response of the RAW264.7 cells was reduced and the M2 polarization of macrophages was promoted on the TNT–GO surface, which may be caused by the reduced ROS production. Consequently, the designed TNT–GO material is promising for implants owing to its excellent inflammation regulation ability. [ABSTRACT FROM AUTHOR]

Lactylation is a process where lactate, a cellular metabolism byproduct, is added to proteins, altering their functions. In the realm of macrophage activation, lactylation impacts inflammatory response and immune regulation. Understanding the effects of lactylation on macrophage activation is vital in lung diseases, as abnormal activation and function are pivotal in conditions like pneumonia, pulmonary fibrosis, COPD, and lung cancer. This review explores the concept of lactylation, its regulation of macrophage activation, and recent research progress in lung diseases. It offers new insights into lung disease pathogenesis and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Depression, projected to be the predominant contributor to the global disease burden, is a complex condition with diverse symptoms including mood disturbances and cognitive impairments. Traditional treatments such as medication and psychotherapy often fall short, prompting the pursuit of alternative interventions. Recent research has highlighted the significant role of gut microbiota in mental health, influencing emotional and neural regulation. Fecalmicrobiota transplantation (FMT), the infusion of fecal matter from a healthy donor into the gut of a patient, emerges as a promising strategy to ameliorate depressive symptoms by restoring gut microbial balance. The microbial-gut-brain (MGB) axis represents a critical pathway through which to potentially rectify dysbiosis and modulate neuropsychiatric outcomes. Preclinical studies reveal that FMT can enhance neurochemicals and reduce inflammatory markers, thereby alleviating depressive behaviors. Moreover, FMT has shown promise in clinical settings, improving gastrointestinal symptoms and overall quality of life in patients with depression. The review highlights the role of the gut-brain axis in depression and the need for further research to validate the longterm safety and efficacy of FMT, identify specific therapeutic microbial strains, and develop targeted microbial modulation strategies. Advancing our understanding of FMT could revolutionize depression treatment, shifting the paradigm toward microbiome-targeting therapies. [ABSTRACT FROM AUTHOR]

Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management. [ABSTRACT FROM AUTHOR]

Over the course of evolution, many proteins have undergone adaptive structural changes to meet the increasing homeostatic regulatory demands of multicellularity. Aminoacyl tRNA synthetases (aaRS), enzymes that catalyze the attachment of each amino acid to its cognate tRNA, are such proteins that have acquired new domains and motifs that enable non-canonical functions. Through these new domains and motifs, aaRS can assemble into large, multi-subunit complexes that enhance the efficiency of many biological functions. Moreover, because the complexity of multi-aminoacyl tRNA synthetase (mARS) complexes increases with the corresponding complexity of higher eukaryotes, a contribution to regulation of homeostatic functions in multicellular organisms is hypothesized. While mARS complexes in lower eukaryotes may enhance efficiency of aminoacylation, little evidence exists to support a similar role in chordates or other higher eukaryotes. Rather, mARS complexes are reported to regulate multiple and variegated cellular processes that include angiogenesis, apoptosis, inflammation, anaphylaxis, and metabolism. Because all such processes are critical components of immune homeostasis, it is important to understand the role of mARS complexes in immune regulation. Here we provide a conceptual analysis of the current understanding of mARS complex dynamics and emerging mARS complex roles in immune regulation, the increased understanding of which should reveal therapeutic targets in immunity and immune-mediated disease. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2), a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, plays a crucial role in cell proliferation, survival, and differentiation. Aberrant HER2 signaling is implicated in various cancers, particularly in breast and gastric cancers, where HER2 overexpression or amplification correlates with aggressive tumor behavior and poor prognosis. HER2-activating mutations contribute to accelerated tumorigenesis and metastasis. This review provides an overview of HER2 biology, signaling pathways, mechanisms of dysregulation, and diagnostic approaches, as well as therapeutic strategies targeting HER2 in cancer. Understanding the intricate details of HER2 regulation is essential for developing effective targeted therapies and improving patient outcomes. [ABSTRACT FROM AUTHOR]

The immune system comprises a complex yet tightly regulated network of cells and molecules that play a critical role in protecting the body from infection and disease. The activity and development of each immune cell is regulated in a myriad of ways including through the cytokine milieu, the availability of key receptors, via tailored intracellular signalling cascades, dedicated transcription factors and even by directly modulating gene accessibility and expression; the latter is more commonly known as epigenetic regulation. In recent years, epigenetic regulators have begun to emerge as key players involved in modulating the immune system. Among these, the lysine methyltransferase DOT1L has gained significant attention for its involvement in orchestrating immune cell formation and function. In this review we provide an overview of the role of DOT1L across the immune system and the implications of this role on health and disease. We begin by elucidating the general mechanisms of DOT1Lmediated histone methylation and its impact on gene expression within immune cells. Subsequently, we provide a detailed and comprehensive overview of recent studies that identify DOT1L as a crucial regulator of immune cell development, differentiation, and activation. Next, we discuss the potential mechanisms of DOT1L-mediated regulation of immune cell function and shed light on how DOT1L might be contributing to immune cell homeostasis and dysfunction. We then provide food for thought by highlighting some of the current obstacles and technical limitations precluding a more in-depth elucidation of DOT1L's role. Finally, we explore the potential therapeutic implications of targeting DOT1L in the context of immune-related diseases and discuss ongoing research efforts to this end. Overall, this review consolidates the current paradigm regarding DOT1L's role across the immune network and emphasises its critical role in governing the healthy immune system and its potential as a novel therapeutic target for immune-related diseases. A deeper understanding of DOT1L's immunomodulatory functions could pave the way for innovative therapeutic approaches which fine-tune the immune response to enhance or restore human health. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD), characterized by clinical sub-phenotypes such as emphysema (E) and chronic bronchitis (CB), is associated with a greater risk of lung cancer (LC). This study aimed to assess the expression patterns of circRNA and their potential functional involvement in LC patients with COPD. A circRNA microarray was used to characterize differentially expressed circRNAs (DEcircRNAs) profiles. A total of 176, 240, 163, and 243 DEcircRNAs were identified in comparisons between CB vs. LC patients (Con), E vs. Con, E vs. CB, and CBE vs. Con, respectively. DEcircRNAs in all comparison groups were primarily associated with immune-related GO terms and were also enriched in immune and inflammatory pathways. In total, 49 DEcircRNAs were significantly correlated with the infiltration of multiple immune cells. Among them, hsa-MROH9_0001 and hsa-RP11-35J10_0013 were positively and negatively correlated with plasma cells and T-cell CD4 memory resting cells, respectively; these two DEcircRNA-sponged miRNAs have good diagnostic performance. WGCNA identified six key circRNAs associated with CB progression. The expression patterns of hsa-MROH9_0001 and circRNA_21729 in E and CB groups were confirmed by RT-qPCR. In conclusion, we reported circRNA profiles and the findings demonstrated that hsa-MROH9_0001 and circRNA_21729 may be potential therapeutic targets for LC with COPD. [ABSTRACT FROM AUTHOR]

Corneal transplantation is an effective treatment for corneal blindness, and it is the only hope for patients with corneal blindness. Cornea has no blood vessels and no lymphatic vessels, which is called immune privilege organ, so the success rate of corneal transplantation is significantly higher than that of other organ transplantation, but the rejection reaction after corneal transplantation is still the main reason for the failure of corneal transplantation. The directional movement of immune cells to lymphoid tissue and inflammatory sites is the mainly immune response after organ transplantation. And the regulatory T cells(Treg)play a key role in immune regulation, which can induce immune tolerance by regulating and inhibiting the activation of effector T cells and reduce the rejection reaction after corneal transplantation. In addition, this review also discussed the effectiveness of applying cordyceps sinensis extract FTY720 to enhance the function of Treg. Based on this, we briefly reviewed the sources, mechanism of action and treatment of Treg after corneal transplantation, so as to provide some reference for the subsequent clinical application transformation and basic research.

Abstract Background Excessive inflammation is a major cause of implant failure. The surface morphology, hydrophilicity, and loading of biomaterials are major properties modulating anti-inflammatory macrophage activation. This paper investigates the regulatory effects of modifying the surface of Titanium dioxide nanotubes (TNTs) with graphene oxide (GO) on the polarization of mouse monocyte macrophages (RAW264.7). Methods TNT was produced by the anodic oxidation of titanium. GO was subsequently electrodeposited on the TNT to obtain a TNT–GO composite. The samples were characterised through scanning electron microscopy (SEM), Raman spectroscopy, and X-ray diffraction. RAW264.7 cells were separately seeded onto the surface of three groups of samples: pure Ti, TNT, and TNT–GO. Under the condition of lipopolysaccharide stimulation, the influence of the sample surfaces on the gene expression profiles was investigated through RNA sequence analysis. In addition, cell spreading was observed through SEM, cell adhesion and proliferation were analysed using the CCK8 assay, and the expression of inflammation-related factors was investigated by ELISA and cellular immunofluorescence staining. The production of reactive oxygen species (ROS) in the RAW264.7 cells on the surface of the three groups was detected via immunofluorescence staining. Results The CCK8 results indicated that the adhesion and proliferation of the RAW264.7 cells were reduced on the TNT and TNT–GO surfaces. ELISA results revealed significant differences in the pro-inflammatory factors tumour necrosis factor-α and interleukin-6 secretion among the three groups at 24 h (p

Abstract Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

In recent years, the incidence and mortality rates of lymphoma have gradually increased worldwide. Tumorigenesis and drug resistance are closely related to intracellular inflammatory pathways in lymphoma. Therefore, understanding the biological role of inflammatory pathways and their abnormal activation in relation to the development of lymphoma and their selective modulation may open new avenues for targeted therapy of lymphoma. The biological functions of inflammatory pathways are extensive, and they are central hubs for regulating inflammatory responses, immune responses, and the tumour immune microenvironment. However, limited studies have investigated the role of inflammatory pathways in lymphoma development. This review summarizes the relationship between abnormal activation of common inflammatory pathways and lymphoma development to identify precise and efficient targeted therapeutic options for patients with advanced, drug-resistant lymphoma. [ABSTRACT FROM AUTHOR]

Recent studies suggest a need for reliable biomarkers enhancing prognosis prediction and treatment strategies in cancer. Here, we performed a data analysis bearing on the expression of SCN3B, voltage-gated sodium channel (VGSC) β3 subunit, as a possible candidate for the development of a glioma biomarker for the first time. This extends our previous review article that mentioned the potential of SCN3B as a prognostic biomarker for glioma survival, further examining its association with existing indicators and immune responses. We utilized clinical and genomic data from multiple glioma cohorts. These include the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). We employed analytical techniques including time-dependent receiver operating characteristic (ROC) analysis, decision curves analysis (DCA), and correlation studies with immune checkpoint markers. Our findings indicate a differential SCN3B expression between glioma grades, and that this significantly correlates with patient survival, particularly in oligodendroglioma subtypes. The DCA curves suggested that the inclusion of SCN3B in the prognostic model would improve decision-making in these subtypes. Moreover, SCN3B expression positively correlated with the presence of key immune cells and negatively correlated with several immune checkpoint inhibitors. This suggests potential roles in modulating immune responses in glioma. Thus, SCN3B emerges as a promising potential prognostic biomarker for glioma, especially for oligodendroglioma. Its dual correlations with prognosis and immune regulation present a compelling case for further experimental and clinical investigations to establish its utility in enhancing glioma management strategies. These findings underscore the importance of integrating novel biomarkers with traditional prognostic models to refine treatment paradigms and improve patient outcomes. [ABSTRACT FROM AUTHOR]

The progression of ulcerative colitis (UC) is associated with immunologic derangement, intestinal hemorrhage, and microbiota imbalance. While traditional medications mainly focus on mitigating inflammation, it remains challenging to address multiple symptoms. Here, a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO2 nanospheres with Cu2O nanoblocks. The resulting CaO2–Cu2O possessed a desirable diameter (291.3 nm) and a uniform size distribution. It could be efficiently internalized by colonic epithelial cells and macrophages, scavenge intracellular reactive oxygen/nitrogen species, and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype. This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles. Rectal administration of CaO2–Cu2O could stanch the bleeding, repair the disrupted colonic epithelial layer, and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation, anti-oxidation, wound healing, and anti-inflammation. Impressively, it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria (e.g., Odoribacter and Bifidobacterium) and decreasing the abundances of harmful bacteria (e.g., Prevotellaceae and Helicobacter). Our gas-driven CaO2–Cu2O offers a promising therapeutic platform for robust treatment of UC via the rectal route.

Inflammatory bowel disease (IBD) represents a heterogenous and complex group of idiopathic chronic inflammatory conditions affecting the gastrointestinal tract and other extraintestinal systems with rising global incidences. The interplay of genetic predisposition and environmental factors contributes to its pathogenesis. Among the key cytokines implicated in IBD molecular alterations, IL-33 stands out for its multifaceted roles in both pathogenesis and repair mechanisms. IL-33, known for its action in initiating immune responses, is closely associated with Th2 immunity and is considered a potent inflammatory factor with dual functions, acting both as a pro-inflammatory cytokine and a transcriptional regulator. Primarily expressed by non-hematopoietic cells in the gastrointestinal tract, IL-33 interacts with its receptor, ST2, to modulate immune responses. In IBD, dysregulated IL-33 expression exacerbates mucosal inflammation, compromising barrier integrity and promoting tissue damage and fibrosis. Additionally, IL-33 plays a complex role in IBD-related colorectal cancer (CRC), affecting tumor progression and angiogenesis. This review summarizes the multifaceted roles of IL-33 in gastrointestinal health and disease, emphasizing its significance in the pathogenesis of IBD and CRC. Moreover, we thought it of interest to provide new insights into potential therapeutic avenues targeting IL-33 signaling for the management of these debilitating conditions.

In order to investigate the immunomodulatory effects of short-term administration of Cordyceps militaris on mice in different states and explore its application value as an immunomodulator, Kunming (KM) mice were randomly divided into a low-dose group (DB), a high-dose group (GB) and a control check group (CK). The mice in the DB and GB groups were continuously gavaged with different doses ofan aqueous suspension of C. militaris powder for 21 days, while the CK group was given the same dose of distilled water. Changes in body mass, organ indexes, serum immunoglobulin G (IgG), IgM, interleukin (IL)-2 and IL-10 levels, the percentages of CD3+CD4+ and CD3+CD8+ T lymphocyte subsets in peripheral blood, intestinal flora composition and Toll-like receptor (TLR)2, TLR4, myeloid differentiation factor (MyD) 88 and nuclear factor (NF)-κB expression in the jejunum were measured. Immunosuppressed mice induced by intraperitoneal injection of 80 mg/kg mb cyclophosphamide solution were intragastrically administered with C. militaris for 21 consecutive days. Immune indexes were detected after 0, 7, 14 and 21 days of administration. The results showed that administration of C. militaris at each dose did not cause significant changes in body mass, organ indexes, serum IgG, IgM, IL-2 and IL-10 levels or the percentages of CD3+CD4+ and CD3+CD8+ T lymphocyte subsets in the peripheral blood of mice (P > 0.05). C. militaris could up-regulate the Shannon index and the number of operational taxonomic units (OTU) in the intestinal flora of mice, and increase the diversity and richness of the intestinal flora. The relative abundances of the probiotics Lactobacillus and Alistipes were significantly increased (P < 0.05). The relative abundances of the inflammation-promoting bacteria Clostridium XIVa, Helicobacter and Lachnospiracea_incertae_sedis were significantly decreased (P < 0.05). The expression of TLR4 in jejunum tissues of mice was significantly decreased by all doses of C. militaris (P < 0.05), and the reduction of NF-κB expression was positively correlated with the dose of C. militaris. C. militaris significantly restored organ damage caused by cyclophosphamide in advance, increased the serum levels of IgM, IgG and IL-2 (P < 0.05), and promoted the proliferation of CD3+CD4+ and CD3+CD8+ T lymphocyte subsets in the peripheral blood of immunosuppressed mice. These results showed that short-term administration of C. militaris could reduce the risk of intestinal inflammation without causing an imbalance in the normal immune status. In conclusion, C. militaris can promote recovery from immunosuppression by enhancing humoral and cellular immunity and thus be developed and utilized as an immunomodulator.

Background: Cancer-associated cachexia is a multi-organ disorder associated with progressive weight loss due to a variable combination of anorexia, systemic inflammation and excessive energy wasting. Considering the importance of immunoregulation in cachexia, it still lacks a complete understanding of the immunological mechanisms in cachectic progression. Aim of review: Our aim here is to describe the complex immunoregulatory system in cachexia. We summarize the effects and translational potential of the immune system on the development of cancer-associated cachexia and we attempt to conclude with thoughts on precise and integrated therapeutic strategies under the complex immunological context of cachexia. Key Scientific Concepts of Review: This review is focused on three main key concepts. First, we highlight the inflammatory factors and additional mediators that have been identified to modulate this syndrome. Second, we decipher the potential role of immune checkpoints in tissue wasting. Third, we discuss the multilayered insights in cachexia through the immunometabolic axis, immune-gut axis and immune-nerve axis.

The identification of diagnostic and therapeutic biomarkers for Alzheimer's Disease (AD) remains a crucial area of research. In this study, utilizing the Weighted Gene Co-expression Network Analysis (WGCNA) algorithm, we identified RHBDF2 and TNFRSF10B as feature genes associated with AD pathogenesis. Analyzing data from the GSE33000 dataset, we revealed significant upregulation of RHBDF2 and TNFRSF10B in AD patients, with correlations to age and gender. Interestingly, their expression profile in AD differs notably from that of other neurodegenerative conditions. Functional analysis unveiled their involvement in immune response and various signaling pathways implicated in AD pathogenesis. Furthermore, our study demonstrated the potential of RHBDF2 and TNFRSF10B as diagnostic biomarkers, exhibiting high discrimination power in distinguishing AD from control samples. External validation across multiple datasets confirmed the robustness of the diagnostic model. Moreover, utilizing molecular docking analysis, we identified dinaciclib and tanespimycin as promising small molecule drugs targeting RHBDF2 and TNFRSF10B for potential AD treatment. Our findings highlight the diagnostic and therapeutic potential of RHBDF2 and TNFRSF10B in AD management, shedding light on novel strategies for precision medicine in AD. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a small subset of patients and relapse can occur in patients who initially respond to the treatment. Recent breakthroughs in this field have identified innate immune checkpoints harnessed by cancer cells to escape immunosurveillance from innate immunity. MHC1 appears to be such a molecule expressed on cancer cells which can transmit a negative signal to innate immune cells through interaction with leukocyte immunoglobulin like receptor B1 (LILRB1). The review aims to summarize the current understanding of MHC1/LILRB1 axis on mediating cancer immune evasion with an emphasis on the therapeutic potential to block this axis for cancer therapy. Nevertheless, one should note that this field is still in its infancy and more studies are warranted to further verify the effectiveness and safety in clinical as well as the potential to combine with existing immune checkpoints. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients’ health and quality of life. Cuproptosis is a newly defined type of programmed cell death that is thought to be involved in the pathogenesis and progression of cardiovascular disease, but the molecular mechanisms involved are not well understood. Therefore, we aimed to identify biomarkers associated with cuproptosis in diabetes mellitus-associated heart failure and the potential pathological mechanisms in cardiomyocytes. Materials: Cuproptosis-associated genes were identified from the previous publication. The GSE26887 dataset was downloaded from the GEO database. Methods: The consistency clustering was performed according to the cuproptosis gene expression. Differentially expressed genes were identified using the limma package, key genes were identified using the weighted gene co-expression network analysis(WGCNA) method, and these were subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The differentially expressed genes for each were identified using limma and the most critical MEantiquewhite4 module was obtained using WGCNA. We then evaluated the intersection of the MEantiquewhite4 output with the three clusters, and obtained the key genes. Results: There were four key genes: HSDL2, BCO2, CORIN, and SNORA80E. HSDL2, BCO2, and CORIN were negatively associated with multiple immune factors, while SNORA80E was positively associated, and T-cells accounted for a major proportion of this relationship with the immune system. Four enriched pathways were found to be associated: arachidonic acid metabolism, peroxisomes, fatty acid metabolism, and dorsoventral axis formation, which may be regulated by the transcription factor MECOM, through a change in protein structure. Conclusion: HSDL2, BCO2, CORIN, and SNORA80E may regulate cardiomyocyte cuproptosis in patients with diabetes mellitus-associated heart failure through effects on the immune system. The product of the cuproptosis-associated gene LOXL2 is probably involved in myocardial fibrosis in patients with diabetes, which leads to the development of cardiac insufficiency. [ABSTRACT FROM AUTHOR]

Zinc finger Asp-His-His-Cys motif-containing (zDHHC) proteins, known for their palmitoyltransferase (PAT) activity, play crucial roles in diverse cellular processes, including immune regulation. However, their non-palmitoyltransferase immunomodulatory functions and involvement in teleost immune responses remain underexplored. In this study, we systematically characterized the zDHHC family in the large yellow croaker (Larimichthys crocea), identifying 22 members. Phylogenetic analysis unveiled that each of the 22 LczDHHCs formed distinct clusters with their orthologues from other teleost species. Furthermore, all LczDHHCs exhibited a highly conserved DHHC domain, as confirmed by tertiary structure prediction. Notably, LczDHHC23 exhibited the most pronounced upregulation following Pseudomonas plecoglossicida (P. plecoglossicida) infection of macrophage/monocyte cells (MO/MΦ). Silencing LczDHHC23 led to heightened pro-inflammatory cytokine expression and diminished anti-inflammatory cytokine levels in MO/MΦ during infection, indicating its anti-inflammatory role. Functionally, LczDHHC23 facilitated M2- type macrophage polarization, as evidenced by a significant skewing of MO/MΦ towards the pro-inflammatory M1 phenotype upon LczDHHC23 knockdown, along with the inhibition of MO/MΦ necroptosis induced by P. plecoglossicida infection. These findings highlight the non-PAT immunomodulatory function of LczDHHC23 in teleost immune regulation, broadening our understanding of zDHHC proteins in host-pathogen interactions, suggesting LczDHHC23 as a potential therapeutic target for immune modulation in aquatic species. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis (MTB), remains one of the most prevalent and deadly infectious diseases worldwide. Currently, there are complex interactions between host cells and pathogens in TB. The onset, progression, and regression of TB are correlated not only with the virulence of MTB but also with the immunity of TB patients. Exosomes are cell-secreted membrane-bound nanovesicles with lipid bilayers that contain a variety of biomolecules, such as metabolites, lipids, proteins, and nucleic acids. Exosome-mediated cell--cell communication and interactions with the microenvironment represent crucial mechanisms through which exosomes exert their functional effects. Exosomes harbor a wide range of regulatory roles in physiological and pathological conditions, including MTB infection. Exosomes can regulate the immune response, metabolism, and cellular death to remodel the progression of MTB infection. During MTB infection, exosomes display distinctive profiles and quantities that may act as diagnostic biomarkers, suggesting that exosomes provide a revealing glimpse into the evolving landscape of MTB infections. Furthermore, exosomes derived from MTB and mesenchymal stem cells can be harnessed as vaccine platforms and drug delivery vehicles for the precise targeting and treatment of TB. In this review, we highlight the functions and mechanisms through which exosomes influence the progression of TB. Additionally, we unravel the critical significance of exosomal constituents in the diagnosis and therapeutic applications of TB, aiming to offer novel perspectives and strategies for combating TB. [ABSTRACT FROM AUTHOR]

Introduction: Emerging proof suggests that Apocynum venetum flowers polysaccharide (AVFP) has immunomodulatory effects in vitro. However, the action mechanism of AVFA is still unclear in vivo. The purpose of this study is to probe into the potential mechanism of AVFA in immunosuppressed mice by investigating organ index, cytokine levels, anti-oxidative stress capacity, transcriptomics, and gut microbiota. Methods: Immunocompromised mice induced by cyclophosphamide (CTX) were divided into six groups. The enzyme-labeled method, hematoxylin and eosin, transcriptomics, and high-throughput sequencing were used to detect the regulatory effects of AVFP on immunocompromised mice and the function of AVFP on the concentration of short-chain fatty acids (SCFAs) by highperformance liquid chromatography (HPLC) analysis. The Spearman correlation analysis was used to analyze the correlation between the intestinal microbiota and biochemical indexes. Results: The experimental results illustrated that AVFP has protective effects against CTX-induced immunosuppression in mice by prominently increasing the organ index and levels of anti-inflammatory factors in serum in addition to enhancing the antioxidant capacity of the liver. Meanwhile, it could also signally decrease the level of pro-inflammatory cytokines in serum, the activity of transaminase in serum, and the content of free radicals in the liver, and alleviate the spleen tissue damage induced by CTX. Transcriptomics results discovered that AVFP could play a role in immune regulation by participating in the NF-κB signaling pathway and regulating the immune-related genes Bcl3, Hp, Lbp, Cebpd, Gstp2, and Lcn2. Gut microbiota results illustrated that AVFP could increase the abundance of beneficial bacteria, reduce the abundance of harmful bacteria, and regulate the metabolic function of intestinal microorganisms while dramatically improving the content of SCFAs, modulating immune responses, and improving the host metabolism. The Spearman analysis further evaluated the association between intestinal microbiota and immunerelated indicators. Conclusion: These findings demonstrated that AVFP could enhance the immune effects of the immunosuppressed mice and improve the body's ability to resist oxidative stress. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor α1 (TNFα) is a pleiotropic cytokine involved in immune regulation and cellular homeostasis, but the crucial role of TNFα in fish gut remained unclear. The current study aimed to evaluate the immunoregulatory function of TNFα1 on gut barrier in a novel hybrid fish (WR), which was produced by crossing white crucian carp (Carassius cuvieri, ♀) with red crucian carp (Carassius auratus red var, ♂). In this study, WR‐tnfα1 sequence was identified, and a high‐level expression was detected in the intestine. Elevated levels of WR‐tnfα1 expressions were detected in immune‐related tissues and cultured fish cells on stimulation. The appearance of vacuolization and submucosal rupture was observed in TNFα1‐treated midgut of WR, along with elevated levels of goblet cell atrophy, whereas no significant changes were detected in most expressions of tight‐junction genes and mucin genes. In contrast, WR receiving gut perfusion with WR‐TNFα1 showed a remarkable decrease in antioxidant status in midgut, whereas the expression levels of apoptotic genes and redox responsive genes increased sharply. These results suggested that TNFα1 could exhibit a detrimental effect on antioxidant defense and immune regulation in the midgut of WR. [ABSTRACT FROM AUTHOR]

Ubiquitin-specific protease 5 (USP5) belongs to the ubiquitin-specific protease (USP) family, which uniquely recognizes unanchored polyubiquitin chains to maintain the homeostasis of monoubiquitin chains. USP5 participates in a wide range of cellular processes by specifically cleaving isopeptide bonds between ubiquitin and substrate proteins or ubiquitin itself. In the process of immune regulation, USP5 affects important cellular signaling pathways, such as NF-κB, Wnt/β-catenin, and IFN, by regulating ubiquitin-dependent protein degradation. These pathways play important roles in immune regulation and inflammatory responses. In addition, USP5 regulates the activity and function of immunomodulatory signaling pathways via the deubiquitination of key proteins, thereby affecting the activity of immune cells and the regulation of immune responses. In the present review, the structure and function of USP5, its role in immune regulation, and the mechanism by which USP5 affects the development of diseases by regulating immune signaling pathways are comprehensively overviewed. In addition, we also introduce the latest research progress of targeting USP5 in the treatment of related diseases, calling for an interdisciplinary approach to explore the therapeutic potential of targeting USP5 in immune regulation. [ABSTRACT FROM AUTHOR]

Simple Summary: For melanoma patients, the most promising curative treatment is immunotherapy. Here, we summarise current immunotherapy strategies and their indications and challenges, and provide future directions of immunotherapy development. Several therapy resistance mechanisms have been described, resulting in primary refractory disease or resistance development in patients. Our increasing knowledge of immune regulation within the tumour microenvironment identifies potential alternate immunotherapy targets, including CD155. CD155 and its receptor, TIGIT, have been shown to be highly expressed in therapy-resistant melanoma cells and interference with both is therefore considered a possible immunotherapeutic strategy. This review describes the immune regulation within the melanoma tumour microenvironment, how and why immunotherapies work, and why CD155 might be an ideal target for the next generation of anti-melanoma immunotherapies. Melanoma is commonly diagnosed in a younger population than most other solid malignancies and, in Australia and most of the world, is the leading cause of skin-cancer-related death. Melanoma is a cancer type with high immunogenicity; thus, immunotherapies are used as first-line treatment for advanced melanoma patients. Although immunotherapies are working well, not all the patients are benefitting from them. A lack of a comprehensive understanding of immune regulation in the melanoma tumour microenvironment is a major challenge of patient stratification. Overexpression of CD155 has been reported as a key factor in melanoma immune regulation for the development of therapy resistance. A more thorough understanding of the actions of current immunotherapy strategies, their effects on immune cell subsets, and the roles that CD155 plays are essential for a rational design of novel targets of anti-cancer immunotherapies. In this review, we comprehensively discuss current anti-melanoma immunotherapy strategies and the immune response contribution of different cell lineages, including tumour endothelial cells, myeloid-derived suppressor cells, cytotoxic T cells, cancer-associated fibroblast, and nature killer cells. Finally, we explore the impact of CD155 and its receptors DNAM-1, TIGIT, and CD96 on immune cells, especially in the context of the melanoma tumour microenvironment and anti-cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Background: For decades, studies have demonstrated the anti‐inflammatory potential of proteins secreted by helminths in allergies and asthma. Previous studies have demonstrated the immunomodulatory capabilities of Succinate Coenzyme A ligase beta‐like protein (SUCLA‐β) derived from Trichinella spiralis, a crucial excretory product of this parasite. Objective: To explore the therapeutic potential of SUCLA‐β in alleviating and controlling ovalbumin (OVA)‐induced allergic asthma, as well as its influence on host immune modulation. Methods: In this research, we utilized the rTs‐SUCLA‐β protein derived from T. spiralis to investigate its potential in mitigating airway inflammation in a murine model of asthma induced by OVA sensitization/stimulation, both pre‐ and post‐challenge. The treatment's efficacy was assessed by quantifying the extent of inflammation in the lungs. Results: Treatment with rTs‐SUCLA‐β demonstrated efficacy in ameliorating OVA‐induced airway inflammation, as evidenced by a reduction in eosinophil infiltration, levels of OVA‐specific Immunoglobulin E, interferon‐γ, interleukin (IL)‐9, and IL‐17A, along with an elevation in IL‐10. The equilibrium between Th17 and Treg cells plays a pivotal role in modulating the abundance of inflammatory cells within the organism, thereby ameliorating inflammation and alleviating symptoms associated with allergic asthma. Conclusions and Clinical Relevance: Our data revealed that T. spiralis‐derived Ts‐SUCLA‐β protein may inhibit the allergic airway inflammation by regulating host immune responses. [ABSTRACT FROM AUTHOR]

The progression of ulcerative colitis (UC) is associated with immunologic derangement, intestinal hemorrhage, and microbiota imbalance. While traditional medications mainly focus on mitigating inflammation, it remains challenging to address multiple symptoms. Here, a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO 2 nanospheres with Cu 2 O nanoblocks. The resulting CaO 2 –Cu 2 O possessed a desirable diameter (291.3 nm) and a uniform size distribution. It could be efficiently internalized by colonic epithelial cells and macrophages, scavenge intracellular reactive oxygen/nitrogen species, and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype. This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles. Rectal administration of CaO 2 –Cu 2 O could stanch the bleeding, repair the disrupted colonic epithelial layer, and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation, anti-oxidation, wound healing, and anti-inflammation. Impressively, it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria (e.g. , Odoribacter and Bifidobacterium) and decreasing the abundances of harmful bacteria (e.g. , Prevotellaceae and Helicobacter). Our gas-driven CaO 2 –Cu 2 O offers a promising therapeutic platform for robust treatment of UC via the rectal route. A versatile gas-propelled nanomotor (CaO 2 –Cu 2 O) was facilely produced to overcome rectal drug delivery barriers and achieve effective synergistic treatment outcomes against ulcerative colitis. [Display omitted] [ABSTRACT FROM AUTHOR]

Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation. [ABSTRACT FROM AUTHOR]

Epilepsy is a progression of development and advancement over time. However, the molecular features of epilepsy were poorly studied from a dynamic developmental perspective. We intend to investigate the key mechanisms in the process of epilepsy by exploring the roles of stage-specifically expressed genes. By using time-course transcriptomic data of epileptic samples, we first analyzed the molecular features of epilepsy in different stages and divided it into progression and remission stages based on their transcriptomic features. 34 stage-specifically expressed genes were then identified by the Tau index and verified in other epileptic datasets. These genes were then enriched for immune-related biological functions. Furthermore, we found that the level of immune infiltration and mechanisms at different stages were different, which may result from different types of immune cells playing leading roles in distinct stages. Our findings indicated an essential role of immune regulation as the potential mechanism of epilepsy development. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) represents a heterogenous and complex group of idiopathic chronic inflammatory conditions affecting the gastrointestinal tract and other extraintestinal systems with rising global incidences. The interplay of genetic predisposition and environmental factors contributes to its pathogenesis. Among the key cytokines implicated in IBD molecular alterations, IL-33 stands out for its multifaceted roles in both pathogenesis and repair mechanisms. IL-33, known for its action in initiating immune responses, is closely associated with Th2 immunity and is considered a potent inflammatory factor with dual functions, acting both as a pro-inflammatory cytokine and a transcriptional regulator. Primarily expressed by non-hematopoietic cells in the gastrointestinal tract, IL-33 interacts with its receptor, ST2, to modulate immune responses. In IBD, dysregulated IL-33 expression exacerbates mucosal inflammation, compromising barrier integrity and promoting tissue damage and fibrosis. Additionally, IL-33 plays a complex role in IBD-related colorectal cancer (CRC), affecting tumor progression and angiogenesis. This review summarizes the multifaceted roles of IL-33 in gastrointestinal health and disease, emphasizing its significance in the pathogenesis of IBD and CRC. Moreover, we thought it of interest to provide new insights into potential therapeutic avenues targeting IL-33 signaling for the management of these debilitating conditions. [ABSTRACT FROM AUTHOR]