细胞与分子免疫学杂志最新文献

Objective To investigate the role and underlying mechanisms of carcinoembryonic antigen-related cell adhesion molecule 4 (CEACAM4) in the immunosuppressive microenvironment of glioblastoma (GBM), to clarify its impact on tumor progression and immune evasion, and to evaluate its potential as a prognostic biomarker and therapeutic target. MethodsCEACAM4 expression, prognostic significance, and immune infiltration profiles were analyzed using The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus(GEO) datasets. CEACAM4 knockdown glioma models were established using shRNA-mediated silencing. The effects of CEACAM4 on tumor cell proliferation, migration, cell cycle progression, and apoptosis were assessed through in vitro assays. Tumor cell-macrophage co-culture systems and xenograft models were used to evaluate the effects of CEACAM4 on myeloid cell recruitment, tumor-associated macrophage (TAM) polarization, and tumor growth in vivo. Results CEACAM4 was significantly upregulated in glioma tissues, particularly in IDH wild-type, 1p/19q non-codeleted, and high-grade tumors. High CEACAM4 expression was associated with poor overall survival. CEACAM4 silencing inhibited glioma cell proliferation, migration, induced G1 cell cycle arrest, and promoted apoptosis. Moreover, CEACAM4 deficiency reduced macrophage recruitment and suppressed TAM polarization toward the immunosuppressive M2 phenotype. Bioinformatics analysis revealed a positive correlation between CEACAM4 expression and immunosuppressive myeloid cell infiltration. In vivo, CEACAM4 knockdown suppressed tumor growth and decreased immunosuppressive myeloid cell accumulation. Conclusion CEACAM4 promotes glioma progression by enhancing malignant tumor phenotypes and shaping a myeloid cell-mediated immunosuppressive tumor microenvironment. CEACAM4 may serve as a prognostic biomarker and a potential therapeutic target for improving immunotherapy efficacy and overcoming treatment resistance in GBM.

Objective Gestational diabetes mellitus (GDM) is associated with long-term endothelial dysfunction of maternal-fetal vessels, and human placental mesenchymal stem cell (hPDMSC)-derived exosomes (PdE) from GDM patients are closely related to the progression of the disease. This study aims to investigate the expression of miR-144-3p in PdE and its effects and the underlying mechanism on vascular endothelial cell dysfunction in GDM. Methods PdE from normal pregnant patients and GDM patients (the Nor-PdE group and the GDM-PdE group) were isolated and collected. Anti-miR144-3p and negative control were transfected into hPDMSC using the Lipofectamine. Then, the PdE were collected and co-cultured with human umbilical vein endothelial cell (HUVEC). Real-time quantitative PCR (qRT-PCR) was performed to detect miR-144-3p expression, while the CCK-8 assay was used to assess HUVEC viability. Transwell^TM assay was performed to analyze cell migration. Matrix gel tube formation assay was carried out to determine tube formation ability. Bioinformatics and dual-luciferase reporter analysis were used to evaluate the targeting relationship between miR-144-3p and suppressors of cytokine signaling 6 (SOCS6). The protein expression of SOCS6 was analyzed by Western blot. Results The PdE from normal pregnant patients and GDM patients were successfully isolated. Compared with Nor-PdE group, the expression levels of miR-144-3p were increased in GDM-PdE group. Moreover, the expression of miR-144-3p was obviously decreased after anti-miR-144-3p treatment. Compared with Nor-PdE group, GDM-PdE treatment dramatically suppressed HUVEC viability, migration and tube formation, these inhibitory effects were markedly attenuated upon miR-144-3p knockdown. Compared with Nor-PdE group, the transcriptional levels of SOCS6 were decreased in HUVECs after treatment with GDM-PdE. Bioinformatics and dual-luciferase reporter analysis confirmed that SOCS6 was a potential target of miR-144-3p. Down-regulation of miR-144-3p obviously increased HUVEC viability, migration and tube formation under GDM-PdE condition, which was abrogated after SOCS6 down-regulation. Conclusion Abnormal high expression of miR-144-3p in GDM-PdE may regulate the dysfunction of vascular endothelial cells by targeting SOCS6, supporting it as a new potential target for PdE in the prevention and treatment of GDM.

Long-lived plasma cells (LLPCs) are primarily found in the CD19^-CD38^hiCD138⁺ plasma cell subset in the human bone marrow. They produce antibodies continuously for several years or even decades after initial infection or vaccination, and are essential for durable anti-infective immunity. Compared to short-lived plasma cells, LLPCs express higher levels of surface molecules such as CD27, CD38, CD138, C-X-C chemokine receptor 4 (CXCR4), interleukin 6 receptor (IL-6R), and B-cell maturation antigen (BCMA). However, specific markers for LLPCs have not been identified yet. Currently, transgenic mouse models like Blimp1-CreERT-TdTomato are primarily used for in vivo tracing and functional studies of these cells. The vast majority of LLPCs originate from germinal center-derived plasmablasts. These plasmablasts migrate from the blood to specific survival niches in the bone marrow. Within these niches, cytokines such as a proliferation-inducing ligand (APRIL) and IL-6 are provided to promote LLPC survival. Simultaneously, key transcription factors such as Blimp-1, X-box binding protein 1 (XBP-1), and IRF4 play pivotal roles in the differentiation, maturation, and long-term maintenance of LLPCs by regulating related gene expression, participating in signaling pathway activation, and enabling metabolic adaptation. The early "imprinting" conferred by the germinal center reaction, together with the bone marrow survival niche, promotes the generation of LLPCs. Furthermore, pathogenic LLPCs that persistently produce autoantibodies contribute to the recurrence of autoimmune diseases like rheumatoid arthritis. Consequently, targeted elimination of these cells has emerged as a critical research direction for treating autoimmune disorders.

TMPRSS2 is a member of a family of proteins localized to the cell membrane and characterized by a conserved serine protease domain. Previous studies have demonstrated its involvement in the initiation and progression of various cancers in the human body. Its serine protease activity can degrade extracellular matrix components, disrupt the integrity of the basement membrane, and promote tumor cell invasion and metastasis. In addition, its expression level is closely related to the degree of immune cell infiltration and may affect tumor immune escape by regulating local inflammatory responses. In terms of viral infection, TMPRSS2 also plays a critical role, especially in the process of coronavirus infection, where it can stimulate the activation of viral particles and enhance infection. Recent studies on COVID-19 have further shown that TMPRSS2-mediated cleavage of the viral spike protein is essential for the activation and entry of the SARS-CoV-2 into the host cells. This review summarizes the current understanding of the structure and function of TMPRSS2, as well as its role in SARS-CoV-2 infection, with the aim of elucidating the underlying mechanisms by which TMPRSS2 facilitates viral entry and propagation within the host. These insights may contribute to the development of targeted therapeutics and vaccines.

Innate immune dysregulation is a common pathological basis for the development and progression of both infectious diseases and various chronic diseases. Drosophila melanogaster, owing to its highly conserved immune system, well-established genetic manipulation tools, and intact in vivo physiological environment, has become an important model for studying human immune-related diseases. This article systematically reviews the latest research progress on the Drosophila model regarding the "infection-innate immune dysregulation-Alzheimer's disease (AD)" axis. Studies using Drosophila models have shown that Gram-positive bacteria and fungi activate the Toll pathway, while Gram-negative bacteria activate the immune deficiency (Imd) pathway, leading to innate immune dysregulation; all of the above pathogen infections are associated with the pathological progression of AD. Peripheral immune dysregulation can mediate cross-organ inflammatory transmission through the gut-brain axis and the oral-gut-brain axis, thereby contributing to the exacerbation of AD pathological damage. The Drosophila tumor necrosis factor α (TNF-α) homolog Eiger, via activation of the tumor necrosis factor-c-Jun N-terminal kinase (TNF-JNK) pathway, mediates peripheral-immune-driven remote central neuroinflammation. These findings suggest that precise regulation of the innate immune system is critical for maintaining organismal homeostasis, and its dysregulation serves as a link between infectious diseases and AD. The Drosophila model provides a unique perspective for dissecting the pathological progression of "infection-innate immune dysregulation-AD," laying a theoretical foundation for AD intervention strategies targeting immune pathways, the gut-brain axis, and the oral-gut-brain axis, and also offering a reference for translational research on innate immunity-related diseases. It should be noted that the above conclusions are mainly based on mechanistic studies in the Drosophila model, and their extrapolation to human AD still requires further validation.

Tumor necrosis factor receptor 2 (TNFR2) is a type I transmembrane glycoprotein receptor expressed in various tumor cells and certain immune cells, particularly regulatory T cells. TNFR2 coordinates multiple signaling pathways to promote tumor initiation and growth, activate immunosuppressive cells, modulate the tumor microenvironment, and facilitate immune escape and tumor progression. In recent years, immunotherapy has been incorporated into the treatment of malignant tumors, yet monotherapy with immune checkpoint inhibitors often suffers from low response rates and frequent immune related adverse events. To further improve therapeutic efficacy, combination immunotherapies have attracted increasing attention. Numerous studies have demonstrated that TNFR2 antibodies exhibit synergistic effects when combined with classical immune checkpoint inhibitors such as programmed death 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) antibodies. Clarifying the role and mechanism of TNFR2 in tumor development is crucial for designing effective combination treatment strategies. This article reviews the expression, function, and mechanisms of TNFR2 in tumors, analyzes the opportunities and challenges in its targeted therapy, and provides new insights and perspectives for clinical oncology.

Objective To investigate the protective mechanism and molecular targets of urolithin A (UA) against alcohol-induced kidney injury. Methods In animal experiments, alcohol-induced kidney injury was established in mice by gavage with 500 mL/L alcohol [5 g/(kg.d)] for three consecutive days, and different doses of UA were administered to evaluate its protective effects. In additional animal and cell intervention experiments, the silent information regulator 1(SIRT1) inhibitor EX-527 was applied. Commercial kits were used to measure kidney function markers creatinine(CREA), blood urea nitrogen (BUN), oxidative stress markers malondialdehyde(MDA), glutathione(GSH), kidney injury molecule 1 (KIM-1), inflammatory cytokines tumor necrosis factor α(TNF-α), interleukin 1β(IL-1β), and iron content. Western blotting was performed to assess the protein expression levels of glutathione peroxidase 4 (GPx4), cystine/glutamate antiporter (system Xc^-) light chain (xCT), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1). Network pharmacology was employed to identify the core ferroptosis targets of UA in protecting against kidney injury. Results Alcohol exposure significantly elevated the levels of CREA, BUN, MDA, KIM-1 and inflammatory cytokines, while decreasing GSH level. UA administration markedly alleviated these changes. In addition, UA significantly suppressed the alcohol-induced increase in iron content and the decreases in GPx4, xCT, Nrf2, and HO-1 protein levels. Seven core target molecules were identified through network pharmacology analysis. Inhibition of SIRT1, the core target, significantly antagonized the protective effects of UA on the Nrf2 pathway, ferroptosis, oxidative kidney injury, and renal function at both cellular and animal levels. Conclusion Alcohol exposure induces significant oxidative injury and impairs kidney function. UA activates the Nrf2 signaling pathway via the core target SIRT1, thereby inhibiting ferroptosis and alleviating alcohol-induced oxidative injury and kidney dysfunction.

Objective To investigate the mechanism by which macrophage migration inhibitory factor (MIF) regulates hypoxia-inducible factor 1α (HIF-1α)-mediated aerobic glycolysis in the pathological process of pulmonary fibrosis. MethodsC57BL/6 mice were divided into four groups: control group, bleomycin (BLM) model group, BLM combined with negative control lentivirus (BLM combined with sh-NC) group, and BLM combined with MIF-shRNA lentivirus (BLM combined with sh-MIF) group. After 28 days of intratracheal administration, lung tissues, bronchoalveolar lavage fluid (BALF), and serum samples were collected. Pathological injury and the degree of fibrosis were assessed by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Glycolytic capacity was evaluated using a lactate dehydrogenase (LDH) activity assay kit, and the end-product content of glycolysis was measured using a lactic acid (LA) assay kit. The protein expression of HIF-1α, 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2) was analyzed by Western blot. Primary mouse lung fibroblasts were divided into the Control group, recombinant MIF protein (rMIF) group, rMIF combined with PHD activator Octyl-α-ketoglutarate (rMIF combined with PHD-Act) group, MIF inhibitor (ISO-1) group, and PHD inhibitor MK-8617 (PHD-IN) groups; as well as the Control group, PHD-IN group, rMIF group, and rMIF combined with PHD-IN groups. The expression of HIF-1α and the protein levels of PHD were detected by RT-qPCR and Western blot, respectively. Cellular metabolic function was assessed by measuring the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) via a fluorescence-based assay kit. Results In animal experiments, compared with the Control group, the BLM group exhibited severe pulmonary fibrosis, along with significantly elevated LDH activity, lactate content, and protein expression of PFKFB3 and PKM2. Interference with MIF expression significantly reversed these changes and alleviated fibrosis. Cellular experiments showed that rMIF significantly upregulated HIF-1α and downregulated the expression of PHD1 and PHD2, an effect that could be reversed by the PHD activator Octyl-α-ketoglutarate. Inhibition of MIF reduced HIF-1α expression, whereas inhibition of PHD directly induced high expression of HIF-1α. Moreover, both rMIF and PHD-IN treatment significantly increased cellular OCR and ECAR. Conclusion MIF stabilizes HIF-1α by inhibiting PHD, thereby driving aerobic glycolysis metabolic reprogramming in lung fibroblasts and promoting the progression of pulmonary fibrosis.

Ankylosing Spondylitis(AS) is a chronic inflammatory disease primarily affecting the spine and sacroiliac joints, with a higher prevalence in young males. Without timely diagnosis and treatment, it can progress to spinal ankylosis, joint function loss, and disability. The exact pathogenesis remains incompletely understood, leaving some patients unresponsive to current treatments and facing poor outcomes. In recent years, the role of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in the pathogenesis of AS has attracted much attention. Upon activation, the NLRP3 inflammasome promotes the activation of cysteine protease 1 (caspase-1), which subsequently cleaves pro-interleukin 1β (pro-IL-1β) into its active form, IL-1β, to aggravate inflammatory responses and bone destruction. This review summarizes the regulatory mechanism of NLRP3 inflammasome in AS and discusses its therapeutic potential. The aim is to provide a rationale for exploring the underlying pathogenesis of AS and for developing novel targeted therapies.