Cell Communication and Signaling最新文献

{"title":"Dynamic changes in macrophage populations and resulting alterations in Prostaglandin E₂ sensitivity in mice with diet-induced MASH.","authors":"Madita Vahrenbrink, C D Coleman, S Kuipers, I Lurje, L Hammerich, D Kunkel, J Keye, S Dittrich, B M Schjeide, R Hiß, J Müller, G P Püschel, J Henkel","doi":"10.1186/s12964-025-02222-y","DOIUrl":"https://doi.org/10.1186/s12964-025-02222-y","url":null,"abstract":"<p><strong>Background: </strong>The transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) is characterized by a chronic low-grade inflammation, involving activation of resident macrophages (Kupffer cells; KC) and recruitment of infiltrating macrophages. Macrophages produce cytokines and, after induction of Cyclooxygenase 2 (COX-2), the key enzyme of prostanoid synthesis, prostaglandin E₂ (PGE₂). PGE₂ modulates cytokine production in an autocrine and paracrine manner, therefore playing a pivotal role in regulating inflammatory processes. Changes in the hepatic macrophage pool during MASLD progression to MASH could influence PGE₂- and cytokine-mediated signaling processes. The aim of this study was to characterize these changes in mice with diet-induced MASH and further elucidate the role of COX-2-dependently formed PGE₂ on the inflammatory response in different macrophage populations of mice with a macrophage-specific COX-2-deletion.</p><p><strong>Methods: </strong>Male, 6-7-week-old wildtype mice were fed either a Standard or high-fat, high-cholesterol MASH-inducing diet for 4, 12 and 20 weeks. Liver macrophages were isolated and analyzed by flow cytometry. For in vitro experiments primary KC, peritoneal macrophages (PM) and Bone-marrow-derived macrophages (BMDM) were isolated from macrophage-specific COX-2-deficient and wildtype mice and treated with lipopolysaccharide (LPS) and/or PGE₂.</p><p><strong>Results: </strong>During MASH-development, the proportion of KC (Clec4F⁺Tim4⁺) decreased, while the proportion of monocyte-derived macrophages (Clec4F^-Tim4^-) and monocyte-derived cells exhibiting a phenotype similar to KC (Clec4F⁺Tim4^-) significantly increased over time. In vitro experiments showed that exogenous PGE₂ completely abrogated the LPS-induced mRNA expression and secretion of tumor necrosis factor-alpha (TNF-α) in primary KC, PM and BMDM from wildtype mice. PM and BMDM, as in vitro models for infiltrating macrophages, were more sensitive to PGE₂ compared to KC. Deletion of COX-2 in all macrophage populations led to an impaired PGE₂-dependent feedback inhibition of TNF-α production. LPSinduced TNF-α mRNA expression was higher compared to the respective wildtype macrophage population.</p><p><strong>Conclusion: </strong>The current study, using a murine MASH model, indicates that PGE₂ may have a protective, anti-inflammatory effect, especially by inhibiting the expression of pro-inflammatory cytokines such as TNFα in infiltrating monocyte-derived macrophages. An inhibition of endogenous PGE₂ synthesis in macrophages by pharmacological inhibition of COX-2 could potentially increase inflammation and promote the progression of MASH.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"227"},"PeriodicalIF":8.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144087093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repression of Connexin26 hemichannel activity protects the barrier function of respiratory airway epithelial cells against LPS-induced alteration.","authors":"Tina Lehrich, Anne Dierks, Masina Plenge, Helena Obernolte, Klaudia Grieger, Katherina Sewald, Frederic Rodriguez, Lucie Malet, Peter Braubach, Florence Bedos-Belval, Anaclet Ngezahayo","doi":"10.1186/s12964-025-02228-6","DOIUrl":"https://doi.org/10.1186/s12964-025-02228-6","url":null,"abstract":"<p><p>In respiratory airway epithelial cells, lipopolysaccharide (LPS) treatment induced an enhancement of connexin 26 (Cx26) hemichannel activity shown by dye uptake experiments after siRNA-mediated knock-down of Cx26. This effect was already observed at infection relevant concentrations (≤ 10 ng/mL LPS) and involved tumor necrosis factor alpha (TNF-α)- and Ca²⁺-dependent signaling. High concentrations (1 µg/mL LPS) reduced the transepithelial electrical resistance (TEER) of Calu-3 cells by 35% within an application time of 3 h followed by a recovery. Parallel to barrier alteration, a reduced tight junction organization rate (TiJOR) of claudin-4 (CLDN4) by 75% was observed within an application time of 3 h. After TEER recovery, CLDN4 TiJOR stayed reduced. Low concentrations (10 ng/mL LPS) required three times repeated application for barrier reduction and CLDN4 TiJOR reduction by 30%. The small molecule CVB4-57, newly published as a potential inhibitor of Cx26 hemichannels, mitigated the effects of LPS on the epithelial barrier function. Molecular docking studies revealed a potential interaction between CVB4-57 and Cx26 thereby reducing its hemichannel activity. We conclude that LPS-related enhancement of Cx26 hemichannel activity acts like a \"molecular scar\" that weakens the lung epithelium, which could be attenuated by agents targeting Cx26 hemichannels.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"226"},"PeriodicalIF":8.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Androgens as the \"old age stick\" in skeletal muscle.","authors":"Giulia Gentile, Ferdinando De Stefano, Carmela Sorrentino, Rosa D'Angiolo, Carmine Lauretta, Pia Giovannelli, Antimo Migliaccio, Gabriella Castoria, Marzia Di Donato","doi":"10.1186/s12964-025-02234-8","DOIUrl":"10.1186/s12964-025-02234-8","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"225"},"PeriodicalIF":8.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induced mitochondrial deficit by NDUFS3 transient silencing reduces RAB7 expression and causes lysosomal dysfunction in pancreatic cancer cells.","authors":"Giulia Girolimetti, Sinforosa Gagliardi, Paola Cordella, Grazia Bramato, Riccardo Di Corato, Roberta Romano, Flora Guerra, Cecilia Bucci","doi":"10.1186/s12964-025-02214-y","DOIUrl":"https://doi.org/10.1186/s12964-025-02214-y","url":null,"abstract":"<p><strong>Background: </strong>RAB7 is a small GTPase with multiple cellular roles, regulating late endocytic trafficking and lysosomal biogenesis, influencing mitochondria-lysosome crosstalk, and contributing to many mitochondrial processes. Mitochondrial dysfunctions are widely reported in cancer and the development of cancer therapeutic strategies targeting mitochondria gained momentum in recent years. Mitochondrial impairment can cause alterations of mitochondria-lysosome crosstalk and can influence lysosomal function. Here, we used cell models of pancreatic cancer, one of the deadliest cancers worldwide, to cause a transient mild mitochondrial deficit lowering NDUFS3 protein levels in order to investigate the consequences on RAB7 and on the late endocytic pathway and, thus, the contribution of the mitochondria-lysosomes communication alterations to cancer progression.</p><p><strong>Methods: </strong>NDUFS3 and RAB7 downregulation was obtained by RNA interference (RNAi). Seahorse assays, Western blot analysis, mitochondrial staining, and Transmission Electron Microscopy (TEM) were used to assess silencing effects on mitochondrial structure and functioning. Western blotting was used to investigate expression of late endocytic pathway proteins and of the invasion marker vimentin. Confocal microscopy was used to analyze the mitochondrial network and lysosomal assessment. Zymography was performed to evaluate the ability to digest the extracellular matrix linked to cancer migration. SRB and colony assays were performed to assess cancer viability and proliferation. Wound healing assay and FluoroBlok membranes were used to determine migration and invasiveness.</p><p><strong>Results: </strong>In pancreatic cancer cells, transient silencing of the NDUFS3 protein caused mitochondrial deficit, slower oxidative metabolism, and mitochondrial morphology alterations. In this context, we observed RAB7 downregulation and impairment of the late endocytic pathway. In addition, NDUFS3-silenced RAB7-downregulated cells showed less invasive tumorigenic potential revealed by reduced levels of vimentin and other Epithelial-to-Mesenchymal Transition proteins, decreased viability, migration and invasiveness. Moreover, we found that modulation of RAB7 expression may regulate vimentin levels and influence mitochondrial morphology and levels of mitochondrial proteins.</p><p><strong>Conclusions: </strong>Overall, our data show that mitochondrial deficit determines alterations of the crosstalk with lysosomes, leading to dysfunctions, and that this process is regulated by RAB7 acting as an oncogene. This highlights the synergic role of RAB7 and mitochondrial dysfunction, focusing on a cellular mechanism that may boost the effect of mitochondrial dysfunction in the cells, leading to the reduction of the tumorigenic potential.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"224"},"PeriodicalIF":8.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3.","authors":"Xinyi Yang, Yuqi Zhu, Xiaying Zhao, Jingna Xun, Xingyu Wang, Yipeng Cheng, Su Xiong, Xingwen Yu, Suixiang Li, Danqing Wang, Zhiliang Hu, Yinzhong Shen, Shibo Jiang, Hongzhou Lu, Gang Wang, Huanzhang Zhu","doi":"10.1186/s12964-025-02221-z","DOIUrl":"10.1186/s12964-025-02221-z","url":null,"abstract":"<p><strong>Background: </strong>Acquired immunodeficiency syndrome (AIDS) cannot be completely cured, and the main obstacle is the existence of viral reservoirs. However, we currently do not fully understand the molecular mechanisms by which HIV-1 latency is established and maintained.</p><p><strong>Methods: </strong>Here, based on engineered chromatin immunoprecipitation (enChIP) technology that using FLAG-tagged zinc finger nucleic acid proteins (FLAG-ZFP) that bind to the HIV-1 L region and chromatin immunoprecipitation, we identified RYBP as a new HIV-1 latency-promoting gene. The effect of RYBP on HIV-1 latency was explored in multiple cell lines and primary latency models through gene knockout methods. Western blot and chromatin immunoprecipitation (ChIP) were used to explore the molecular mechanism of RYBP in promoting HIV-1 latency.</p><p><strong>Results: </strong>Disruption of RYBP gene can activate latent HIV-1 in different latent cell lines and primary latent cell models. Mechanistically, the HIV-1 long terminal repeats (LTR) region binding protein Yin Yang 1 (YY1) can recruit RYBP to the HIV-1 L region. Then, RYBP can further recruit KDM2B, thereby promoting the increased ubiquitination level of H2AK119 and decreases the level of H3K4me3, to decrease HIV-1 L transcriptional elongation and enter a latent state. At the same time, during the stage of viral transcription and replication, Tat protein can inhibit the expression of RYBP, promoting viral transcription and replication. Finally, we found that the H2AK119ub inhibitor PRT4165 can promote latent HIV-1 activation and has good synergy with reported latent reactivating agents.</p><p><strong>Conclusion: </strong>These results provide mechanistically new insights into a critical role of RYBP in the regulation of histone modification and H2AK119ub may be directly targeted to control HIV reservoirs.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"222"},"PeriodicalIF":8.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ER stress and/or ER-phagy in drug resistance? Three coincidences are proof.","authors":"Sameer Kumar Panda, Ibone Rubio Sanchez-Pajares, Ayesha Rehman, Vitale Del Vecchio, Luigi Mele, Sandhya Chipurupalli, Nirmal Robinson, Vincenzo Desiderio","doi":"10.1186/s12964-025-02232-w","DOIUrl":"10.1186/s12964-025-02232-w","url":null,"abstract":"<p><p>Cancer is influenced by the tumor microenvironment (TME), which includes factors such as pH, hypoxia, immune cells, and blood vessels. These factors affect cancer cell growth and behavior. The tumor microenvironment triggers adaptive responses such as endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and autophagy, posing a challenge to cancer treatment. The UPR aims to restore ER homeostasis by involving key regulators inositol-requiring enzyme-1(IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Additionally, ER-phagy, a selective form of autophagy, eliminates ER components under stress conditions. Understanding the interplay between hypoxia, ER stress, UPR, and autophagy in the tumor microenvironment is crucial for developing effective cancer therapies to overcome drug resistance. Targeting the components of the UPR and modulating ER-phagy could potentially improve the efficacy of existing cancer therapies. Future research should define the conditions under which ER stress responses and ER-phagy act as pro-survival versus pro-death mechanisms and develop precise methods to quantify ER-phagic flux in tumor cells.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"223"},"PeriodicalIF":8.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential regulation of mTORC2 signalling by type I and type II calreticulin (CALR) driver mutations of myeloproliferative neoplasm.","authors":"Saadia Naseer, Aditi Singh, Saurabh Shrivastva, Rishi Kant Singh, Shayeri Chowdhury, Chinmoy Sankar Dey, Anita Roy","doi":"10.1186/s12964-025-02212-0","DOIUrl":"10.1186/s12964-025-02212-0","url":null,"abstract":"<p><p>Calreticulin (CALR) is an endoplasmic reticulum chaperone. Frameshift mutations in CALR were discovered in patients with myeloproliferative neoplasm showing increased platelet counts. The frameshift was observed in the last exon of CALR, leading to a novel C-terminal tail. Calreticulin mutations were categorised into Type I and Type II depending upon the extent of retention of CALR WT sequences. Clinically, Type I mutations induced myelofibrosis, while Type II mutations were associated with early onset of the disease. Both mutations induced ligand-independent activation of the thrombopoietin receptor (TpoR) and consequently enhanced platelet production. However, no specific difference in signalling mechanism could be demonstrated between them. Using over-expression of CALR WT, CALR ∆52 (Type I) and CALR ins5 (Type II) in HEK cells, we showed that Type I CALR mutations downregulated the basal mTORC2 signalling without affecting mTORC1. The decrease in basal mTORC2 signalling was attributed to CALR ∆52-induced increased expression of c-JUN through occupation of the enhancer sequences of jun. Furthermore, increased c-JUN expression decreased the expression of RICTOR, a component of mTORC2. Strikingly, overexpression of RICTOR or knockdown of c-JUN reversed the inhibitory effect of CALR ∆52 on mTORC2 activity. Finally, we demonstrated that CALR ∆52 decreased the glucose uptake and cellular ATP levels in a c-JUN-mTORC2-dependent manner. These findings not only contribute to our understanding of the molecular mechanisms underlying mutant CALR driven myeloproliferative neoplasm but also provide potential therapeutic targets against the disease.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"221"},"PeriodicalIF":8.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual inhibition of GTP-bound KRAS and mTOR in lung adenocarcinoma and squamous cell carcinoma harboring KRAS G12C.","authors":"Masaoki Ito, Yoshihiro Miyata, Shoko Hirano, Nagisa Morihara, Misako Takemoto, Fumiko Irisuna, Kei Kushitani, Kenichi Suda, Junichi Soh, Yukio Takeshima, Yasuhiro Tsutani, Morihito Okada","doi":"10.1186/s12964-025-02187-y","DOIUrl":"https://doi.org/10.1186/s12964-025-02187-y","url":null,"abstract":"<p><strong>Background: </strong>Kirsten rat sarcoma (KRAS) mutations are somatic variants in lung adenocarcinoma. One of the most prevalent mutations, G12C, has led to the clinical approval of targeted inhibitors for advanced stages in lung cancer. Research has increasingly focused on the efficacy of combination therapies that target multiple tumorigenic pathways. Cases harboring KRAS G12C mutation are heterogenous. We explored alternative changes in genetic pathways and evaluated the effectiveness of combination therapy using several types of cell lines and KRAS inhibitors.</p><p><strong>Methods: </strong>We comprehensively investigated genetic changes induced by KRAS G12C inhibition using RNA sequences and the candidate to inhibit in combination therapy was explored. Three lung cancer cell lines (two adenocarcinoma and one squamous cell carcinoma) and three KRAS G12C inhibitors (AMG 510, MRTX849, and ARS-1620) were used. KRAS G12C and candidate gene were simultaneously inhibited in cell lines and the efficiency of combination therapy was evaluated using clonogenic assays and MTS assay. Pathway activation was assessed via western blotting. A combination index (CI) < 0.8 was considered statistically synergistic.</p><p><strong>Results: </strong>RNA sequences revealed treatment with two of the three KRAS G12C inhibitors led to a significant increase in mTOR expression across all three cell lines. mTOR was targeted in combination therapy; each KRAS G12C inhibitor and mTOR inhibitor (RAD001) combination exhibited synergism (CI < 0.8) in MTS and clonogenic assays. Single inhibition of mTOR induced activation of guanosine triphosphate (GTP)-RAS, thereby activating the RAS-MEK-ERK and PI3K-AKT-mTOR pathways in WB, suggesting mTOR activation is crucial for KRAS-driving lung cancer. A combination strategy targeting KRAS G12C and mTOR abrogated GTP-RAS, pmTOR (Ser2448), and pERK (Thr202/Tyr204) more efficiently.</p><p><strong>Conclusions: </strong>KRAS G12C inhibitor plus RAD001 consistently revealed synergism. Targeting KRAS G12C and mTOR abrogates the RAS-MEK-ERK and PI3K-AKT-mTOR pathways. Our data suggests that a combined strategy targeting GTP-bound KRAS G12C and mTOR shows promise for primary lung cancers with KRAS G12C mutations. This approach may also be effective even for lung cancers harboring KRAS G12C mutation but having different profiles.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"220"},"PeriodicalIF":8.2,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1α regulated GLUT1-mediated glycolysis enhances Treponema pallidum-induced cytokine responses.","authors":"Shun Xiong, Zhaoping Liu, Jiangchen Yao, Shaobin Huang, Xuan Ding, Han Yu, Ting Lin, Xiaohong Zhang, Feijun Zhao","doi":"10.1186/s12964-025-02211-1","DOIUrl":"https://doi.org/10.1186/s12964-025-02211-1","url":null,"abstract":"<p><p>Syphilis, caused by Treponema pallidum (Tp), represents a significant public health challenge. The clinical manifestations of syphilis are attributed to local inflammatory responses induced by Tp, notably monocyte infiltration into local lesions and the secretion of inflammatory cytokines. However, the mechanisms driving cytokine production in response to Tp infection remain largely unknown. Given that increased glycolysis is associated with inflammatory responses, we aimed to investigate the role of glycolysis in Tp-induced secretion of inflammatory cytokines. In this study, we found that Tp promotes the secretion of inflammatory cytokines IL-6, IL-8, and CCL2 from monocytes while enhancing glycolysis through increased GLUT1 plasma membrane expression and glucose uptake. Importantly, inhibiting glycolysis and GLUT1 reduced the Tp-induced secretion of monocyte inflammatory cytokines. Additionally, Tp significantly increased HIF-1α expression and induced its nuclear translocation, thereby promoting glycolysis by upregulating the expression of GLUT1 and LDHA glycolytic enzymes. Knockdown of HIF-1α inhibits Tp-induced monocyte cytokine secretion, highlighting the crucial role of HIF-1α-mediated glycolysis in the cytokine response to Tp. Also, expression of HIF-1α and an increase in glycolysis were confirmed in patients with syphilis. In conclusion, we demonstrated that HIF-1α-regulated GLUT1-mediated glycolysis enhances inflammatory cytokine secretion following Tp infection. Our findings not only elucidate the mechanism of glycolysis in Tp-induced inflammatory responses in monocytes but also contribute to the development of a potential biomarker in syphilis diagnosis and treatment.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"219"},"PeriodicalIF":8.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accumulation of long-chain unsaturated fatty acids in the airway inflammatory microenvironment drives eosinophil etosis and corticosteroid resistance.","authors":"Yurong Bai, Pengda Fang, Shasha Li, Zhenhao Xiao, Wenyi Chen, Wenlong Li, Xinyue Wang, Jingyuan Chen, Yue Li, Junhai Chen, Weiqiang Huang, Xin Luo, Shigeharu Ueki, Deyu Fang, Qintai Yang, Yana Zhang","doi":"10.1186/s12964-025-02217-9","DOIUrl":"https://doi.org/10.1186/s12964-025-02217-9","url":null,"abstract":"<p><strong>Background: </strong>Eosinophilic inflammation is a feature of chronic rhinosinusitis with nasal polyps (CRSwNP). Patients with eosinophilic CRSwNP (ENP) tend to be refractory and prone to recurrence. Although there is increasing evidence linking lipid metabolic irregularities to eosinophilia, the particular lipid responsible for promoting eosinophilic inflammation and the precise molecular mechanisms involved remain unclear.</p><p><strong>Methods: </strong>Lipidomic atlas and metabolic pathway enrichment were identified by liquid chromatography-tandem mass spectrometry and RNA sequencing, respectively. Eosinophil extracellular trap cell death (EETosis) was detected by immunofluorescence microscopy and transmission electron microscopy. Functional analyses were performed on purified eosinophils.</p><p><strong>Results: </strong>The unbiased lipidomic atlas identified a specific accumulation in long-chain fatty acids (LCFAs) in ENP. Consistently, RNA-seq analysis confirmed the enrichment in long-chain unsaturated fatty acid metabolism pathway in ENP. In this lipid-rich airway inflammatory environment, EETosis including ETotic eosinophils, EETs release and Charcot-Leyden crystals (CLCs) generation was enhanced in ENP, and associated with disease severity. Further, we found that both saturated and unsaturated LCFAs, such as arachidonic acid, are critical fuel sources to trigger eosinophil activation and filamentous DNA release, whereas only arachidonic acid could induce crystalline Galectin10 (CLCs). Mechanistically, arachidonic acid induces EETosis through a mechanism independent of reactive oxygen species but the IRE1α/XBP1s/PAD4 pathway. Both the long-acting dexamethasone and short-acting hydrocortisone, while facilitate eosinophil apoptosis, are ineffective to block arachidonic acid-induced EETosis.</p><p><strong>Conclusions: </strong>Our findings demonstrate a previously unknown role of the LCFA arachidonic acid in mediating EETosis and glucocorticoid insensitivity to drive ENP progression, which may lead to novel insights regarding the treatment of patients with refractory eosinophilic inflammation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"217"},"PeriodicalIF":8.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}