Molecular immunology最新文献

{"title":"NLRP3 regulates macrophage function by M-CSF/M-CSFR signaling in acute radiation-induced lung injury","authors":"Yuqing Feng ,&nbsp;Jiao Kong ,&nbsp;Wanyue Sun ,&nbsp;Yan Li ,&nbsp;Fule Ren ,&nbsp;Xuetong Sun ,&nbsp;Mingxi Li ,&nbsp;Ying Liu ,&nbsp;Shilong Sun ,&nbsp;Haiyan Qin","doi":"10.1016/j.molimm.2025.05.009","DOIUrl":"10.1016/j.molimm.2025.05.009","url":null,"abstract":"<div><div>Alveolar macrophages are the most abundant macrophages in the healthy lungs and are important players in maintaining lung homeostasis as well as orchestrating tissue repair after injury. Many studies have proved that the initiation, development and progression of acute radiation-induced lung injury are associated with alveolar macrophages. However, lung-associated macrophages function and developmental processes in acute radiation-reduced lung injury remain elusive. To investigate the role of NLRP3 in radiation-reduced lung injury, we established wild-type and NLRP3^-/- mice models, and we found that the extent of pneumonia reduced in NLRP3^-/- IR group. In in vivo experiments, we observed a decrease in the number of macrophages in NLRP3^-/- group. At the same time, in in vitro experiments we have found that macrophages are more easily polarized toward the M2 after radiation in NLRP3^-/- group compared with the control group. Our findings reveal that NLRP3 affects the differentiation and chemotaxis of alveolar macrophages through M-CSF/M-CSFR signalling at the onset of radiation-induced lung injury.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 213-224"},"PeriodicalIF":3.2,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144105616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TSPAN15 enhances EMT-mediated metastasis of HCC by promoting autophagy through BTRC-mediated PDCD4 degradation","authors":"Zicheng Shao ,&nbsp;Qingya Hao ,&nbsp;Jie Chen ,&nbsp;Yuhua Lu","doi":"10.1016/j.molimm.2025.05.012","DOIUrl":"10.1016/j.molimm.2025.05.012","url":null,"abstract":"<div><h3>Background</h3><div>Cumulative evidence shows that Tetraspanin 15 (TSPAN15) shows a high degree of consistency in a variety of tumor characteristics, which has attracted extensive attention from researchers. We used TSPAN15 as a starting point to explore the role and mechanism of TSPAN15 in in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>Using database analysis, recombinant plasmid transfection technology, transwell, autophagic flux analysis and western blotting, the effects of TSPAN15 on autophagy, invasion, epithelial-mesenchymal transition (EMT) of HCC cells, and tumor growth and metastasis were elucidated after silencing TSPAN15 in HCC cells. The effect of TSPAN15 on tumor growth was detected by using xenograft model of nude mice.</div></div><div><h3>Results</h3><div>Based on the online database and immunohistochemistry analysis, it was found that the mRNA and protein expression of TSPAN15 in HCC tissues was significantly higher than that in normal liver tissues or adjacent non-cancerous tissues. High expression of TSPAN15 was an independent risk factor for poor prognosis in TCGA-LIHC patients. TSPAN15 silencing inhibited HCC autophagy and autophagy-induced migration, invasion and EMT as well as tumor growth and metastasis. Mechanistically, TSPAN15 contributed to programmed cell death 4 (PDCD4) proteasomal degradation through physical interaction with beta-transducin repeat containing (BTRC), thus activing autophagy. Rescue experiments revealed that PDCD4 effectively inhibited TSPAN15-induced autophagy, migration, invasion and EMT.</div></div><div><h3>Conclusion</h3><div>Abnormally expressed TSPAN15 promotes the degradation of tumor suppressor gene PDCD4 through ubiquitination, thereby promoting autophagy and autophagy-mediated EMT and metastasis of HCC cells, demonstrating the importance of TSPAN15 in the molecular etiology of HCC and its potential therapeutic value.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 203-212"},"PeriodicalIF":3.2,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical characteristics and outcomes of pediatric anterior and intermediate uveitis in China","authors":"Nan Sun ,&nbsp;Min Zhang ,&nbsp;Zheng Liu ,&nbsp;Xiaomin Zhang","doi":"10.1016/j.molimm.2025.05.013","DOIUrl":"10.1016/j.molimm.2025.05.013","url":null,"abstract":"<div><h3>Purpose</h3><div>To summarize the clinical characteristics of pediatric anterior and intermediate uveitis (PAIU) and evaluate the effectiveness of vitreous cell (VC) grading and multimodal imaging techniques in the diagnosis and management of PAIU cases.</div></div><div><h3>Methods</h3><div>This retrospective study analyzed data on demographic characteristics, clinical features, treatment methods, and responses. Imaging tests included optical coherence tomography (OCT) and ultra-widefield fluorescein angiography (UWFFA) to assess retinal thickness, peripheral vascular leakage (PVL), and other inflammatory indicators.</div></div><div><h3>Results</h3><div>Eighty-eight PAIU cases accounted for 23 % of pediatric uveitis (median age at onset: 10.5 years (Range 1.0–16.0); 90.9 % bilateral, 96.6 % idiopathic). Initial symptoms included eye redness (74.4 %), blurred vision (27.5 %), pain (23.8 %), and photophobia (21.3 %), but 20.6 % were asymptomatic. Initial evaluations revealed active anterior chamber cell (ACC) and mild VC. UWFFA revealed diffuse PVL in 76.2 % of patients and limited PVL in 23.8 %. OCT revealed a significant positive correlation between retinal thickness and ACC or VC grading (P &lt; 0.05). Compared to OCT, VC grading demonstrates greater sensitivity to disease progression during late-stage follow-up. Most eyes (87.7 %) achieved inflammation control with median treatment of 3.3 months (Interquartile range 1.2–6.2), short referral time and initial methotrexate use being independent prognostic factors. However, 32.2 % of eyes experienced the first recurrent episode during a median follow-up of 15.3 months (Interquartile range, 5.7–23.8); long referral time was an independent prognostic factor for relapse.</div></div><div><h3>Conclusion</h3><div>Patients with PAIU present with inflammation involving both anterior segment, vitreous and peripheral retina and need systemic treatment. Monitoring of VC, macular edema, and PVL using multimodal imaging techniques are crucial for early diagnosing and long-term management of PAIU.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 194-202"},"PeriodicalIF":3.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Total free lipids from MDR strain of Mycobacterium tuberculosis “M” reduce T cell activation and CTL activity in healthy individuals","authors":"María Mercedes Bigi ,&nbsp;Belén Imperiale ,&nbsp;Marcelo Soria ,&nbsp;Beatriz López ,&nbsp;Fabiana Bigi ,&nbsp;Silvia de la Barrera","doi":"10.1016/j.molimm.2025.05.007","DOIUrl":"10.1016/j.molimm.2025.05.007","url":null,"abstract":"<div><div>Increasing evidence highlights the role of cell wall components in the effectiveness of different <em>Mycobacterium tuberculosis</em> (<em>Mtb)</em> strains in modulating host immune response. We previously demonstrated that the outbreak multidrug-resistant strain M displays a distinctive lipid profile in its cell envelope compared to the closely related sporadic strain 410. Both strains markedly differ in their ability to induce fully functional CD8⁺ T cells because of low CD69 signaling and impaired CD4⁺ T cell help. In this study, we evaluated the impact of extractable lipids (LP) from M (LP-M) and 410 (LP-410) on the activation and functionality of T cells from healthy individuals. PBMCs were cultured alone or with <em>Mtb</em> in the presence or absence of LP-M, LP-410, or LP from CD1551 mutants in polymorphic genes between M and 410. Then, surface CD69 and intracytoplasmic IL-2 (after 3 days of culture), as well as surface CD107 expression (after 6 days of culture) were determined in T cells by flow cytometry. In contrast to LP-410, LP-M induced low expression of CD69 and IL-2 in CD4⁺/CD8⁺ cells and of CD107 in CD8⁺ cells. Besides, LP from <em>Mtb</em> strains mutated in <em>Rv1861c</em> and <em>Rv3787c</em> genes inhibited H37Rv-induced T cell response without causing cell death. Thus, our results suggest that LP-M likely through mutations in <em>Rv1861</em> and <em>Rv3787c,</em> inhibits the activation and functionality of T cells from PPD+ healthy human donors and might partially contribute to the development of immune evasion mechanisms in the M strain.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 182-193"},"PeriodicalIF":3.2,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The m6A demethylase FTO controls Th1 differentiation and immunity against infections","authors":"Zhihong Yao ,&nbsp;Lina Sun ,&nbsp;Yang Gao ,&nbsp;Yanhong Su ,&nbsp;Boxiao He ,&nbsp;Yao Ge ,&nbsp;Chen Yang ,&nbsp;Xiaoxuan Jia ,&nbsp;Anjun Jiao ,&nbsp;Chenming Sun ,&nbsp;Baojun Zhang","doi":"10.1016/j.molimm.2025.05.004","DOIUrl":"10.1016/j.molimm.2025.05.004","url":null,"abstract":"<div><div>Antigen-specific effector CD4⁺ T cells are critical for defense against exogenous pathogens. However, the epigenetic mechanisms underlying CD4⁺ T cell immune responses, particularly RNA modifications, remain incompletely understood. In this study, we employed a T cell-specific deletion of the fat mass and obesity-associated protein (FTO), a key N6-methyladenosine (m⁶A) demethylase, to elucidate its role in CD4⁺ T cell mediated immunity. Our findings demonstrate that FTO is essential for maintaining CD4⁺ T cell immune responses and protective functions. Specifically, FTO deficiency restricts the expansion of CD4⁺ T helper (Th)1 effector cells following antigen challenge and results in decreased expression of T-bet and IFN-γ in Th1 cells. Additionally, FTO deficient CD4⁺ T cells exhibit impaired pathogen elimination. Collectively, our study reveals a novel epigenetic regulatory mechanism in supporting CD4⁺ T cell differentiation, providing new insights into the post-transcriptional regulation of CD4⁺ T cell immunity and highlighting the potential for therapeutic strategies.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 172-181"},"PeriodicalIF":3.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144068150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted p38 mitogen-activated protein kinase inhibition potently augment inflammatory responses of human macrophages toward Staphylococcus aureus","authors":"Astrid Lund ,&nbsp;David Moffat ,&nbsp;Stine Dam Jepsen ,&nbsp;Claus Desler ,&nbsp;Lars Andresen ,&nbsp;Søren Bregenholt ,&nbsp;Venkat Reddy ,&nbsp;Søren Skov","doi":"10.1016/j.molimm.2025.05.010","DOIUrl":"10.1016/j.molimm.2025.05.010","url":null,"abstract":"<div><div>Antibiotic-resistant <em>Staphylococcus aureus (S. aureus)</em> is a growing challenge for human health and novel treatment options are needed. Here we examine a novel therapeutic approach against persistent <em>S. aureus</em> infections based on monocyte/macrophage specific inhibition of the p38α mitogen-activated protein kinase activity. Since systemic p38α kinase inhibition cause aberrant toxicity, we used the myeloid specific p38α kinase inhibitor, MPL-5821. P38α kinase inhibition caused a potent increase in the pro-inflammatory profile of human macrophages after exposure to <em>S. aureus</em>, including upregulation of M1-markers and induction of pro-inflammatory cytokines including IFN-γ, TNF-α, IL-1β, IL12p70, IL-6 and IL-8, as well as an increase in phagocytic capacities. These pro-inflammatory signals were only seen after combined <em>S. aureus</em> exposure and p38α inhibition. Macrophages are often regulated by changes in intracellular metabolism. In agreement with this, the combination of <em>S. aureus</em> exposure and p38α inhibition led to specific changes in glycolytic and mitochondrial activity within the responding macrophages. Our study thus unravels a novel and specific activation of macrophages that augment their response toward <em>S. aureus</em>, without causing aberrant inflammation. This constitutes a unique non-antibiotic therapeutic approach that can potentially be used against persistent <em>S. aureus</em> infection.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 145-155"},"PeriodicalIF":3.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cordycepin ameliorates high glucose-induced proliferation, inflammation, and extracellular matrix deposition in glomerular mesangial cells through Smad7-dependent manner","authors":"Weiyu Han ,&nbsp;Shuang Chen ,&nbsp;Beiting Ma ,&nbsp;Zhewen Deng ,&nbsp;Jiaqi Li ,&nbsp;Chenglun Tang ,&nbsp;Zhengxin Lu ,&nbsp;Shanshan Li ,&nbsp;Qi Zhang ,&nbsp;Bo Ma","doi":"10.1016/j.molimm.2025.05.011","DOIUrl":"10.1016/j.molimm.2025.05.011","url":null,"abstract":"<div><div>Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease. The extracellular matrix deposition is potent pathogenic factors of renal fibrosis and injury. Cordycepin (Cor), a natural nucleoside compound from <em>Cordyceps militaris</em>, has been demonstrated reno-protective properties. Nevertheless, the role and underlying mechanism of Cor in DN have not been studied extensively. This study aimed to investigate the renal protective effects and mechanism of Cor on diabetic mouse models and high glucose (HG) induced-mouse glomerular mesangial cells (GMCs). The results of the biochemical indicators indicated that Cor could ameliorate renal dysfunction, as evidenced by reductions in serum creatinine, blood urea nitrogen, and urinary protein. Histological evaluation further confirmed that Cor ameliorated renal pathological changes, including mesangial matrix expansion, glomerular basement membrane thickening, glomerulosclerosis, and fibrillar collagen deposition. Additionally, Cor alleviated cell proliferation and fibrosis induced by high glucose in GMCs. Mechanistically, Cor upregulated the expression of Smad7, suppressed TGF-β/Smad pathway activation and its downstream NOX4-mediated NLRP3 inflammasome. Furthermore, knockdown of Smad7 by shRNA transfection abrogated the inhibiting effects of Cor in high glucose-induced GMCs. These findings suggested that Cor represented a promising therapeutic candidate for mitigating renal damage in diabetic nephropathy. The underlying mechanism involved the enhancement of Smad7 expression, which in turn suppresses TGF-β/Smad signaling and NOX4-mediated NLRP3 inflammasome activation.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 156-171"},"PeriodicalIF":3.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phillyrin for sepsis-related acute lung injury: A potential strategy suppressing GSK-3β","authors":"Guangli Yang ,&nbsp;Weifu Tan ,&nbsp;Lijun Yan ,&nbsp;Qiaocong Lao ,&nbsp;Wujuan Zheng ,&nbsp;Hongyan Ding ,&nbsp;Jingtao Yu ,&nbsp;Yong Liu ,&nbsp;Liyi Zou ,&nbsp;Maorun Guo ,&nbsp;Linzhong Yu ,&nbsp;Xiangjun Zhou ,&nbsp;Wei Li ,&nbsp;Liling Yang","doi":"10.1016/j.molimm.2025.04.017","DOIUrl":"10.1016/j.molimm.2025.04.017","url":null,"abstract":"<div><div>The efficacy of clinical drugs for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains suboptimal. Phillyrin (PHN), a compound derived from Forsythia, is believed to alleviate sepsis-related ALI/ARDS; however, its mechanisms are not fully elucidated. In this study, we screened 8331 target genes associated with ALI/ARDS from public databases and identified six hub genes relevant to PHN treatment: AKT1, GSK-3β, PPP2CA, PPP2CB, PPP2R1A, and AR. Receiver operating characteristic analysis and single-cell sequencing analysis revealed the expression of AKT1, GSK-3β, PPP2CA, PPP2CB, and PPP2R1A were markedly elevated. Molecular docking and dynamics simulations indicated that PHN forms a structurally stable complex with glycogen synthase kinase-3β (GSK-3β). Mendelian randomization analyses suggested that PHN, as a potent GSK-3β inhibitor, may promote M2 macrophage polarization and reduce neutrophil recruitment. We validated these findings through in vivo and in vitro experiments, demonstrating that PHN lowers iNOS levels and raises MMR levels by downregulating GSK-3β mRNA expression and protein activity during lipopolysaccharide (LPS)-induced macrophage inflammation. Additionally, PHN inhibited GSK-3β mRNA expression and protein activity, reducing NF-κB-p65 nuclear translocation in LPS-induced zebrafish inflammation and mice ALI. This inhibition decreased levels of TNF-α and IL-6, increased IL-10 levels, promoted M2 macrophage polarization, suppressed neutrophil recruitment, and ultimately ameliorated ALI/ARDS. In conclusion, our results indicate that PHN effectively alleviates LPS-induced ALI/ARDS by suppressing GSK-3β signaling.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 115-136"},"PeriodicalIF":3.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Truncated IFI16 mRNA transcripts can control its viral DNA defense activity","authors":"Jorge Martinez-Laso ,&nbsp;Isabel Cervera ,&nbsp;Marina S. Martinez-Carrasco ,&nbsp;Clara Sánchez-Menéndez ,&nbsp;Manuel Remesal ,&nbsp;Guiomar Casado-Fernández ,&nbsp;Elena Mateos ,&nbsp;Luis Lemus-Aguilar ,&nbsp;Montserrat Torres ,&nbsp;Mayte Coiras","doi":"10.1016/j.molimm.2025.05.005","DOIUrl":"10.1016/j.molimm.2025.05.005","url":null,"abstract":"<div><div>One of the most well-known viral receptors of the group called named ALRs is IFI16 (interferon-inducible protein 16) that are responsible for responses against viral dsDNA. A pyrin domain (PYD), two HIN domains, a NLS (nuclear localization sequence), and S/T/P repeats region form the structure of IFI16. Five alternatively transcripts have been described (V1, V2, V9, V4 and Vβ) that encode five isoforms (IFI16-iso1, 2, 3, 4 and β) with different structure, localization, and function. Another four transcripts (V3, V5, V6, and V8) and 12 predicted transcripts (VX1-VX7, VX1.1-VX5.1) have also been registered in the Genebank without any structural study. In the present study, we have performed a complete study of the presence of the IFI16 transcripts in a healthy population. All the alternative transcripts described except six of the so-called predicted transcripts were found, furthermore, two new transcripts (V10, V11) were described. The main mechanisms for the regulation of mRNA from IFI16 expression are due to the insertion of non-coding regions and the loss of almost all exons. A total of nine different isoforms were found and the corresponding protein models were constructed to establish the modification of its functionality to form inflammasomes or the binding to viral DNA.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 137-144"},"PeriodicalIF":3.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gastric cancer cells shuttle lactate to induce inflammatory CAF-like phenotype and function in bone marrow-derived mesenchymal stem cells","authors":"Feng Huang ,&nbsp;Xiaoli Cao ,&nbsp;Jingyu Mei ,&nbsp;Chen Wu ,&nbsp;Wei Zhu ,&nbsp;Li Sun ,&nbsp;Chun Dai ,&nbsp;Mei Wang","doi":"10.1016/j.molimm.2025.05.002","DOIUrl":"10.1016/j.molimm.2025.05.002","url":null,"abstract":"<div><div>Metabolic reprogramming, exemplified by the \"Warburg effect,\" is a hallmark of human cancers, leading to lactate buildup in tumors. Bone marrow-derived mesenchymal stem cells (BM-MSCs), key contributors to cancer-associated fibroblasts (CAFs), integrate into gastric cancer stroma through interactions with cancer cells. However, the role of lactate in activating BM-MSCs in this context remains unclear. Herein, exogenous lactate induced a pro-tumorigenic phenotype in BM-MSCs, which was blocked by AZD3965. Gastric cancer cells released more lactate under hypoxia than normoxia. While normoxic gastric cancer cells could educate BM-MSCs, hypoxic cells were more effective. However, the effects of the supernatant from gastric cancer cells in both conditions were significantly reduced by AZD3965. Similarly, prevention of lactate production by oxamic acid sodium significantly reduced the effects observed. Lactate-activated BM-MSCs showed NF-κB signaling activation, increased IL-8 secretion, and no change in TGF-β signaling. These activated BM-MSCs promoted gastric cancer cell migration and invasion through IL-8 secretion and enhanced resistance to CD8 + T cell cytotoxicity by upregulating PD-L1. Collectively, gastric cancer cells induce an iCAF-like phenotype and function in BM-MSCs through a lactate shuttle mechanism, emphasizing the role of metabolic reprogramming in cellular communication that fosters a supportive tumor microenvironment. Targeting lactate-related pathways may provide new therapeutic strategies to hinder BM-MSCs' supportive roles in gastric cancer.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"183 ","pages":"Pages 93-103"},"PeriodicalIF":3.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}