Cell Communication and Signaling最新文献

{"title":"ApoE2 affects insulin signaling in the hippocampus and spatial cognition of aged mice in a sex-dependent manner.","authors":"Yu Wang, Hanchen Liu, Yijuan Ye, Wenting Fang, Anlan Lin, Xiaoman Dai, Qinyong Ye, Xiaochun Chen, Jing Zhang","doi":"10.1186/s12964-025-02093-3","DOIUrl":"10.1186/s12964-025-02093-3","url":null,"abstract":"<p><p>Apolipoprotein E (APOE) has garnered significant attention as one of the most influential genetic risk factors for Alzheimer's disease (AD). While the pathogenic role of APOE4 in sporadic AD has been extensively studied, research on the protective effects of the APOE2 genotype and its underlying mechanisms remains limited. Additionally, the existence of sex differences in the protective effects of ApoE2 continues to be a topic of debate. In this study, we utilized humanized ApoE2- and ApoE3- target replacement mice to examine the sex-specific effects of ApoE2 on cognition. Compared with female ApoE3 mice, we found significantly lower spatial cognitive ability and impaired hippocampal synaptic ultrastructure in aged female ApoE2 mice, accompanied by reduced insulin signaling of the hippocampus. Further analyses by target metabolomics and transcriptomic analyses revealed that female ApoE2 mice exhibit an age-related decline in hippocampal inositol levels, and that alterations in inositol levels lower insulin signaling. Importantly, inositol supplementation was found to alleviate peripheral glucose intolerance, enhance insulin signaling, and ultimately improve cognitive function. Interestingly, these differences were not observed between male ApoE2 and ApoE3 mice. The research findings not only provide new insights into the impact of ApoE2 on cognition but also offer a new strategy for cognitive improvement through inositol supplementation in older women.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"112"},"PeriodicalIF":8.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517405","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":"Regulation of CXCR4 function by S1P₁ through heteromerization.","authors":"Hyun-Tae Kim, Jae-Yeon Jeong, Won-Ki Huh","doi":"10.1186/s12964-025-02099-x","DOIUrl":"10.1186/s12964-025-02099-x","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The trafficking of immune cells between lymphoid organs and circulation depends on gradients of CXCL12 and sphingosine-1-phosphate (S1P), mediated through their cognate receptors C-X-C chemokine receptor type 4 (CXCR4) and S1P receptor type 1 (S1P&lt;sub&gt;1&lt;/sub&gt;). S1P&lt;sub&gt;1&lt;/sub&gt; facilitates the egress of hematopoietic stem cells and lymphocytes by counteracting CXCR4-mediated retention signals. However, the molecular mechanisms underlying this interplay remain poorly understood. In this study, we uncover CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromerization and explore their functional interactions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Bimolecular fluorescence complementation (BiFC) assay, proximity ligation assay (PLA), and quantitative bioluminescence resonance energy transfer (BRET) assay were employed to detect CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromerization. Functional properties of the heteromers were assessed using cAMP assay, G protein activation, β-arrestin recruitment, ligand binding, calcium mobilization, and transwell migration assays. S1P&lt;sub&gt;1&lt;/sub&gt;-overexpressing Jurkat T cells were generated via lentiviral transduction, while S1P&lt;sub&gt;1&lt;/sub&gt;-deficient KARPAS299 cells and β-arrestin1/2-deficient HEK293A cells were constructed using the CRISPR/Cas9 system.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromerization was observed in HEK293A cells overexpressing both receptors. The S1P/S1P&lt;sub&gt;1&lt;/sub&gt; axis interfered with CXCR4-mediated signaling, while CXCR4 did not affect S1P&lt;sub&gt;1&lt;/sub&gt;-mediated signaling, indicating a unidirectional modulation of CXCR4 by S1P&lt;sub&gt;1&lt;/sub&gt;. CXCL12 binding to CXCR4 remained unchanged in the presence of S1P&lt;sub&gt;1&lt;/sub&gt;, and interference of CXCL12-induced Gα&lt;sub&gt;i&lt;/sub&gt; activation by S1P&lt;sub&gt;1&lt;/sub&gt; was observed in β-arrestin1/2-deficient cells. BRET analysis revealed that S1P&lt;sub&gt;1&lt;/sub&gt; interfered with CXCR4-Gα&lt;sub&gt;i&lt;/sub&gt; pre-association and CXCR4 oligomerization, both of which are critical for CXCR4 function. Domain-swapping experiments identified transmembrane domain 3 of S1P&lt;sub&gt;1&lt;/sub&gt; as essential for this modulation. In Jurkat T cells overexpressing S1P&lt;sub&gt;1&lt;/sub&gt;, CXCR4-mediated signaling and cell migration were diminished, whereas these functions were enhanced in S1P&lt;sub&gt;1&lt;/sub&gt;-deficient KARPAS299 cells. Co-activation of S1P&lt;sub&gt;1&lt;/sub&gt; attenuated CXCL12-induced migration, while pretreatment with S1P or FTY720-phosphate increased CXCR4-mediated migration by downregulating surface S1P&lt;sub&gt;1&lt;/sub&gt; in KARPAS299 cells. In primary T cells, PLA confirmed CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromerization, and S1P interfered with CXCL12-induced migration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study identifies CXCR4-S1P&lt;sub&gt;1&lt;/sub&gt; heteromers and demonstrates a unidirectional modulation of CXCR4 by S1P&lt;sub&gt;1&lt;/sub&gt;. S1P&lt;sub&gt;1&lt;/sub&gt; affects CXCR4 function by disrupting its G protein pre-association and oligomerization. These findings underscore the regulatory role of the S1P/S1P&lt;sub&gt;1&lt;/sub&gt; axis i","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"111"},"PeriodicalIF":8.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517451","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":"CXXC5 function blockade promotes diabetic wound healing through stimulating fibroblast and vascular endothelial cell activation.","authors":"Yutong Chen, Xiaofeng Ding, Zhouji Ma, Shuai Shao, Heyan Huang, Yumeng Huang, Beizhi Wang, Hao Zhang, Qian Tan","doi":"10.1186/s12964-025-02097-z","DOIUrl":"10.1186/s12964-025-02097-z","url":null,"abstract":"<p><strong>Background: </strong>Extracellular matrix (ECM) and angiogenesis are critical controls of wound regeneration, and their dysfunction delays diabetes recovery. CXXC5 belongs to the CXXC protein family that can regulate the function of human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs); However, awareness of its functional role remains limited.</p><p><strong>Methods: </strong>Mice were divided into control (CON), diabetic (DM), diabetic + KY19382 (DM + KY19382), and diabetic + vehicle (DM + Vehicle) groups. HDFs and HUVECs were stimulated under different CXXC5 conditions and mice were treated with KY19382, followed by the application of assays including Western blotting (WB), immunofluorescence (IF) and quantitative reverse transcription-PCR (qRT-PCR) to assess wound healing and molecular signaling.</p><p><strong>Results: </strong>Mice in DM had fewer blood vessels, a slower wound healing rate, and more disrupted collagen than CON. Application of KY19382 improved these conditions, which promoted fibroblast activation and vascularization in high glucose environments and DM. Mechanistically, blocking CXXC5 promotes Wnt/β-catenin-mediated stabilization by reducing the binding of the deterrent factor CTBP1 to β-catenin, which induces dermal fibroblast activation and facilitates HUVECs tube formation and migration via VEGFA/VEGFR2 and NFκB signaling pathways. KY19382 promotes HUVECs activation by blocking CTBP1 transcription to activate the NFκB signaling pathway, thus wound re-vascularization.</p><p><strong>Conclusion: </strong>CXXC5 is an essential regulatory factor of wound healing and a prospective therapeutic target for treating chronic wound damage in diabetes.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"108"},"PeriodicalIF":8.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506202","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":"LRSAM1 mediated the degradation of intracellular Vibrio through the ubiquitination-autophagy-lysosome pathway in oyster.","authors":"Wenwen Yang, Jiejie Sun, Qiuyan Guo, Wei Wang, Jinyuan Leng, Lingling Wang, Linsheng Song","doi":"10.1186/s12964-025-02111-4","DOIUrl":"10.1186/s12964-025-02111-4","url":null,"abstract":"<p><p>The leucine rich repeat and sterile alpha motif containing 1 (LRSAM1) as E3 ligase recognizes bacteria and generates a ubiquitin signal to initiate the autophagy process. In the present study, LRSAM1 was identified from the Pacific oyster Crassostrea gigas (designed as CgLRSAM1), which was able to recognize various pathogen-associated molecular patterns and bacteria and directly ubiquitinate Vibrio splendidus. V. splendidus was co-localized with CgLRSAM1 and ubiquitin after invading haemocytes, and the ubiquitinated V. splendidus was then internalized into haemocyte lysosomes by p62-LC3-mediated autophagy. In haemocytes of CgLRSAM1-RNAi oysters, the activation of CgLC3 was enhanced after V. splendidus stimulation. While the co-localization values of V. splendidus with ubiquitin, CgLC3 and lysosomes all decreased significantly after V. splendidus stimulation. These results indicated that CgLRSAM1 functioned as E3 ligase responsible for anti-Vibrio-associated ubiquitination and regulated the degradation of bacteria through the ubiquitination-autophagy-lysosome pathway.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"110"},"PeriodicalIF":8.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506205","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":"Emerging functions of Plakophilin 4 in the control of cell contact dynamics.","authors":"Lisa Müller, Mechthild Hatzfeld","doi":"10.1186/s12964-025-02106-1","DOIUrl":"10.1186/s12964-025-02106-1","url":null,"abstract":"<p><p>Plakophilin 4 (PKP4, also called p0071) is a unique armadillo family protein localized at adherens junctions that acts as a scaffold protein capable of clustering cadherins. PKP4 also regulates cadherin recycling which is vital to enable junction dynamics. In addition, PKP4 controls the mechanical properties of cells by regulating actin filament organization through small Rho-GTPases. In this setting, PKP4 controls the localization and activity of specific guanine exchange factors (GEFs) and of their opponents, the GTPase activating proteins (GAPs). Through the formation of multiprotein complexes with Rho-GTPases, their regulators and their effectors, PKP4 controls the spatio-temporal activity of Rho signaling to regulate cell adhesion and cell mechanics. In keratinocytes, PKP4 prevents differentiation and at the same time dampens proliferation. This is, in part achieved through an interaction with the Hippo pathway, which controls the activity of the transcriptional co-factors YAP and TAZ. In a feedback loop, YAP/TAZ modulate PKP4 localization and function. Here, we review the various functions of PKP4 in cell signaling, cell mechanics, cell adhesion and growth control. We discuss how these functions converge in the regulation of cell adhesion dynamics to allow cells to adapt to their changing environment and enable proliferation, delamination but, at the same time, guarantee cell barrier function.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"109"},"PeriodicalIF":8.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506204","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":"Targeting A2M-LRP1 reverses uterine spiral artery remodeling disorder and alleviates the progression of preeclampsia.","authors":"Zhengrui Huang, Ping Zhang, Ruiping Chen, Lu Sun, Jingyun Wang, Ruiling Yan, Mengyuan Liu, Yuzhen Ding, Jian Wang, Jiachun Wei, Wanchang Yin, Xinyao Lu, Guang Wang, Xuesong Yang, Ruiman Li","doi":"10.1186/s12964-025-02060-y","DOIUrl":"10.1186/s12964-025-02060-y","url":null,"abstract":"<p><strong>Background: </strong>Patients with early-onset preeclampsia (EOPE) have a most severe disease state. a2-macroglobulin (A2M) play a crucial role in the pathogenesis of EOPE, but its molecular basis and therapeutic potential remain unclear. This study aimed to elucidate the mechanisms of A2M in EOPE progression and explore the potential of A2M in the treatment of EOPE.</p><p><strong>Methods: </strong>A2M-Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) blocker Receptor-associated protein (RAP) were utilized to alleviate the disease symptom of lipopolysaccharide (LPS) induced preeclampsia rat model. RNA-seq data sourced from public databases and morphological experiments were utilized to examine the relationship between the main fate of smooth muscle cell (SMC) during uterine spiral artery remodeling (SPA-REM) and A2M. Proteomic sequencing analysis of A2M overexpression rat placenta was used to identify the underlying mechanism. Further, LC-MS/MS analysis combined with Co-immunoprecipitation (Co-IP) was used to examine the interacting between A2M and underlying mechanism.</p><p><strong>Results: </strong>Single-cell analysis and morphological experimental results suggest that SMC phenotype switching disorder is the main fate of SMC in the pathological of SPA-REM disorder, and A2M has a causal relationship with this process. Proteomic sequencing data suggest that A2M participates in this process through the RhoA-GTPase pathway, further experimental data provide evidences that A2M can directly upregulate RhoA-GTPase. Cytological and explant experiments suggest that RAP has better efficacy than A2M knockdown AAV vector, finally the efficacy of RAP was verified in the rat model of preeclampsia.</p><p><strong>Conclusion: </strong>SMC A2M promotes the progression of preeclampsia by directly upregulating RhoA-GTPase. Our findings also reveal that A2M serve as a potential target for EOPE and provide a preliminary therapy for inhibit the combination of A2M-LRP1.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"107"},"PeriodicalIF":8.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493972","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":"NK cell immunopotentiators-loaded nanoliposomes enhance ADCC effect for targeted therapy against HER2-positive breast cancer.","authors":"Ruoxin Du, Changqing Cao, Dong Fan, Guodong Li, Shuangpeng Pu, Xinyao Xu, Mengmeng Liu, Gege Shi, Yuxin Wu, Qiang Hao, Yuan Gao, Juliang Zhang, Huadong Zhao, Cun Zhang","doi":"10.1186/s12964-024-02023-9","DOIUrl":"10.1186/s12964-024-02023-9","url":null,"abstract":"<p><p>Trastuzumab serves as a cornerstone of first-line therapy for HER2-positive (HER2⁺) breast cancer; however, a significant challenge arises due to the emergence of resistance within approximately one year of commencement of treatment, particularly in advanced cases with metastatic disease where its efficacy is limited. Our investigation into the tumor tissue from HER2⁺ breast cancer patients, employing single-cell sequencing and bioinformatics analysis, has elucidated a crucial mechanism underlying the reduced responsiveness of tumors to trastuzumab: the diminished infiltration and activity of natural killer (NK) cells within the tumor microenvironment (TME). To counteract this impediment, we meticulously selected two potent immune-modulating peptides TKD and IP-10p, which are known to recruit and enhance the activity of NK cells. Through in vitro experiments, we substantiated that bolstering the tumor infiltration and activity of NK cells can lead to an enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effect, thereby amplifying the anti-tumor activity of trastuzumab. Building upon this foundational discovery, we further designed HER2-targeted pH-sensitive nanoliposomes to encapsulate TKD and IP-10p peptides. The novel designed nanoliposomes were strategically employed in conjunction with NK cell supplement therapy within a HER2⁺ breast cancer model undergoing trastuzumab treatment, yielding a striking anti-tumor response and indicating that the combination strategy effectively reinvigorated the anti-tumor immune response. In essence, this study not only underscores a critical link between the diminished ADCC effect mediated by trastuzumab and the development of resistance in HER2⁺ breast cancer but also demonstrates leveraging HER2-targeted nanoliposomes to deliver NK cell immunopotentiators can significantly enhance the functional activity of NK cells and their infiltration within the TME, culminating in improved antitumor efficacy of trastuzumab through the augmentation of the ADCC effect.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"106"},"PeriodicalIF":8.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476864","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":"p53-regulated SESN1 and SESN2 regulate cell proliferation and cell death through control of STAT3.","authors":"Alexander Haidurov, Andrei O Zheltukhin, Anastasiya V Snezhkina, George S Krasnov, Anna V Kudryavtseva, Andrei V Budanov","doi":"10.1186/s12964-025-02104-3","DOIUrl":"10.1186/s12964-025-02104-3","url":null,"abstract":"<p><p>Sestrin1 and Sestrin2 (SESN1&2) are evolutionarily conserved, stress-responsive proteins that regulate cell growth and viability. The primary target of Sestrins is the mTORC1 protein kinase, an activator of anabolic processes and an autophagy inhibitor. Our previous studies showed that inactivating SESN1&2 in lung adenocarcinoma A549 cells accelerates cell proliferation and confers resistance to cell death without affecting mTORC1 activity, suggesting that SESN1&2 modulate cellular processes via mTORC1-independent mechanisms. This work describes a new mechanism through which SESN1&2 regulate cell proliferation and death by suppressing the STAT3 transcription factor. Normally activated in response to stress and inflammation, STAT3 is frequently overactivated in human cancers. This overactivation promotes the expression of pro-proliferative and anti-apoptotic genes that drive carcinogenesis. We demonstrate that SESN1&2 inactivation stimulates STAT3 by downregulating the PTPRD phosphatase, a protein responsible for STAT3 dephosphorylation. Our study demonstrates that SESN1&2 deficiency may cause STAT3 activation and facilitate carcinogenesis and drug resistance, making SESN1&2 reactivation a potential cancer treatment strategy.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"105"},"PeriodicalIF":8.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476865","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":"The efferocytosis dilemma: how neutrophil extracellular traps and PI3K/Rac1 complicate diabetic wound healing.","authors":"Yulin Xie, Jiaman Yang, He Zhu, Rongya Yang, Yunlong Fan","doi":"10.1186/s12964-025-02092-4","DOIUrl":"10.1186/s12964-025-02092-4","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The resolution of apoptotic cells (ACs) is crucial for wound healing and tissue remodeling and is often impaired by persistent inflammation. This study aimed to elucidate the impact of neutrophil extracellular traps (NETs) on diabetic wound healing by targeting the phosphoinositide 3-kinase/Ras-related C3 botulinum toxin substrate 1 (PI3K/Rac1) signaling pathway, which is pivotal for macrophage efferocytosis.</p><p><strong>Methods: </strong>A streptozotocin-induced diabetic mouse model was used to assess the impact of NETs on efferocytosis in vivo. The effects of NETs on macrophage efferocytosis and wound healing were evaluated using specific inhibitors and agonists targeting the PI3K/Rac1 pathway. In vitro, macrophages from diabetic wounds or cell lines (Raw264.7) were treated with NETs and a panel of pharmacological agents of the PI3K/Rac1 pathway to evaluate macrophage efferocytosis.</p><p><strong>Results: </strong>NETs were found to inhibit macrophage efferocytosis, resulting in delayed clearance of ACs that accumulate within the wounds. Inhibition of NET formation in diabetic mice rescued impaired efferocytosis, accompanied by reactivation of PI3K and Rac1 in macrophages. Moreover, pharmacological agents targeting the PI3K/Rac1 pathway restored NETs-induced impairment in efferocytosis, leading to rapid wound healing. Raw264.7 cells exhibited elevated activation levels of PI3K and Rac1 when co-cultured with ACs in vitro. Nevertheless, this signaling activation was inhibited when cultured in a NETs-conditioned medium, leading to attenuated efferocytosis.</p><p><strong>Conclusions/interpretation: </strong>Targeting NETs and the PI3K/Rac1 pathway emerges as a potential therapeutic strategy to enhance healing in diabetic wounds by promoting macrophage efferocytosis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"103"},"PeriodicalIF":8.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476961","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":"Vitamin D impedes eosinophil chemotaxis via inhibiting glycolysis-induced CCL26 expression in eosinophilic chronic rhinosinusitis with nasal polyps.","authors":"Weiqiang Huang, Yana Zhang, Yue Li, Junming Ma, Xia Li, Yanjie Jiang, Jianqi Wang, Haotian Wu, Xiaohong Chen, Zizhen Huang, Xifu Wu, Xiaoping Lai, Donglin Li, Lihong Chang, Gehua Zhang","doi":"10.1186/s12964-025-02078-2","DOIUrl":"10.1186/s12964-025-02078-2","url":null,"abstract":"<p><strong>Background: </strong>Chronic rhinosinusitis with nasal polyps (CRSwNP) is likely to relapse due to aberrant eosinophil infiltration. The deficiency of Vitamin D (VD) is associated with increased eosinophil infiltration in eosinophilic oesophagitis. However, the role of VD in eosinophilic CRSwNP (ECRSwNP) remains unclear. This study aims to explore the effects of VD on eosinophil chemotaxis in ECRSwNP and the underlying mechanisms.</p><p><strong>Methods: </strong>Human nasal mucosal tissues were collected from the control group, patients with non-ECRSwNP and those with ECRSwNP. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of VD and CCL26 in the nasal mucosa, plasma, or human primary nasal epithelial cells (hNECs). hNECs and eosinophils from patients were cultured to investigate the effect of VD on eosinophil chemotaxis and CCL26 expression via eosinophil migration assay, Western blot, and ELISA. Transcriptome sequencing, pathway enrichment analysis, Western blot and immunohistochemical staining were used to determine the key signaling pathway involved in eosinophil chemotaxis.</p><p><strong>Results: </strong>A significant decrease in VD levels was observed in the nasal mucosa of patients with ECRSwNP, which correlated with increased local eosinophil infiltration. Furthermore, pathway enrichment analysis suggested that glycolysis signaling was promoted in the ECRSwNP group, verified by enhanced expression of glycolytic key enzymes that were positively correlated with eosinophil infiltration in nasal mucosa from patients with ECRSwNP. VD suppressed eosinophil chemotaxis in vitro by inhibiting CCL26 expression. Glycolysis regulated CCL26 expression via the ERK pathway and lactate, which promoted the expression and stability of CCL26 protein. VD attenuated glycolysis, leading to decreased production of lactate and inactivation of the ERK pathway. The decrease in lactate production suppressed eosinophil chemotaxis. Moreover, the ERK pathway activator reversed the inhibitory effect of VD on eosinophil chemotaxis.</p><p><strong>Conclusions: </strong>VD impedes eosinophil chemotaxis by inhibiting glycolysis - induced CCL26 expression via attenuating the activation of the ERK pathway and reducing lactate production. VD supplementation may be a novel strategy to treat ECRSwNP.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"104"},"PeriodicalIF":8.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477145","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}