CellsPub Date : 2024-10-21DOI: 10.3390/cells13201745
Lisa Griesel, Patrick Kaleja, Andreas Tholey, Marcus Lettau, Ottmar Janssen
{"title":"Comparative Analysis of Extracellular Vesicles from Cytotoxic CD8<sup>+</sup> αβ T Cells and γδ T Cells.","authors":"Lisa Griesel, Patrick Kaleja, Andreas Tholey, Marcus Lettau, Ottmar Janssen","doi":"10.3390/cells13201745","DOIUrl":"https://doi.org/10.3390/cells13201745","url":null,"abstract":"<p><strong>Background: </strong>Although belonging to different branches of the immune system, cytotoxic CD8<sup>+</sup> αβ T cells and γδ T cells utilize common cytolytic effectors including FasL, granzymes, perforin and granulysin. The effector proteins are stored in different subsets of lysosome-related effector vesicles (LREVs) and released to the immunological synapse upon target cell encounter. Notably, in activated cells, LREVs and potentially other vesicles are continuously produced and released as extracellular vesicles (EVs). Presumably, EVs serve as mediators of intercellular communication in the local microenvironment or at distant sites.</p><p><strong>Methods: </strong>EVs of activated and expanded cytotoxic CD8<sup>+</sup> αβ T cells or γδ T cells were enriched from culture supernatants by differential and ultracentrifugation and characterized by nanoparticle tracking analyses and Western blotting. For a comparative proteomic profiling, EV preparations from both cell types were isobaric labeled with tandem mass tags (TMT10plex) and subjected to mass spectrometry analysis.</p><p><strong>Results: </strong>686 proteins were quantified in EV preparations of cytotoxic CD8<sup>+</sup> αβ T cells and γδ T cells. Both populations shared a major set of similarly abundant proteins, while much fewer proteins presented higher abundance levels in either CD8<sup>+</sup> αβ T cells or γδ T cells. To our knowledge, we provide the first comparative analysis of EVs from cytotoxic CD8<sup>+</sup> αβ T cells and γδ T cells.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495933","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}
CellsPub Date : 2024-10-21DOI: 10.3390/cells13201741
Karolina Szymanska, Edyta Rytelewska, Ewa Zaobidna, Marta Kiezun, Marlena Gudelska, Grzegorz Kopij, Kamil Dobrzyn, Ewa Mlyczynska, Patrycja Kurowska, Barbara Kaminska, Anna Nynca, Nina Smolinska, Agnieszka Rak, Tadeusz Kaminski
{"title":"Correction: Szymanska et al. The Effect of Visfatin on the Functioning of the Porcine Pituitary Gland: An In Vitro Study. <i>Cells</i> 2023, 12, 2835.","authors":"Karolina Szymanska, Edyta Rytelewska, Ewa Zaobidna, Marta Kiezun, Marlena Gudelska, Grzegorz Kopij, Kamil Dobrzyn, Ewa Mlyczynska, Patrycja Kurowska, Barbara Kaminska, Anna Nynca, Nina Smolinska, Agnieszka Rak, Tadeusz Kaminski","doi":"10.3390/cells13201741","DOIUrl":"https://doi.org/10.3390/cells13201741","url":null,"abstract":"<p><p>In the original publication [...].</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495936","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}
CellsPub Date : 2024-10-21DOI: 10.3390/cells13201743
Zahra Fanaei-Kahrani, Christoph Kaether
{"title":"Asparagine614 Determines the Transport and Function of the Murine Anti-Aging Protein Klotho.","authors":"Zahra Fanaei-Kahrani, Christoph Kaether","doi":"10.3390/cells13201743","DOIUrl":"https://doi.org/10.3390/cells13201743","url":null,"abstract":"<p><p>Klotho is an anti-aging protein whose deletion significantly reduces lifespan in mice, while its over-expression increases lifespan. Klotho is a type-I transmembrane protein that is N-glycosylated at eight positions within its ectodomain. Our study demonstrates that N-glycosylation or mutation at position N614, but not at N161, N285, or N346 in mouse Klotho, is critically involved in the transport of Klotho out of the endoplasmic reticulum (ER). Consequently, while wild-type Klotho-EGFP as well as the N-glycosylation mutants N161Q, N285Q, and N346Q were present at the plasma membrane (PM), only small amounts of the N614Q Klotho-EGFP were present at the PM, with most of the protein accumulating in the ER. Protein interactome analysis of Klotho-EGFP N614Q revealed increased interactions with proteasome-related proteins and proteins involved in ER protein processing, like heat shock proteins and protein disulfide isomerases, indicative of impaired protein folding. Co-immunoprecipitation experiments confirmed the interaction of Klotho-EGFP N614Q with ER chaperons. Interestingly, despite the low amounts of Klotho-EGFP N614Q at the PM, it efficiently induced FGF receptor-mediated ERK activation in the presence of FGF23, highlighting its efficacy in triggering downstream signaling, even in limited quantities at the PM.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495912","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}
CellsPub Date : 2024-10-21DOI: 10.3390/cells13201744
Hao Gu, Kang Xu, Zhao Yu, Zufeng Ren, Fan Chen, Changfan Zhou, Wei Zeng, Hongyan Ren, Yulong Yin, Yanzhen Bi
{"title":"N<sup>6</sup>-Methyladenosine RNA Modification Regulates the Differential Muscle Development in Large White and Ningxiang Pigs.","authors":"Hao Gu, Kang Xu, Zhao Yu, Zufeng Ren, Fan Chen, Changfan Zhou, Wei Zeng, Hongyan Ren, Yulong Yin, Yanzhen Bi","doi":"10.3390/cells13201744","DOIUrl":"https://doi.org/10.3390/cells13201744","url":null,"abstract":"<p><p>N6-methyladenosine (m<sup>6</sup>A) is the most common modification in eukaryotic RNAs. Growing research indicates that m<sup>6</sup>A methylation is crucial for a multitude of biological processes. However, research on the m<sup>6</sup>A modifications in the regulation of porcine muscle growth is lacking. In this study, we identified differentially expressed genes in the neonatal period of muscle development between Large White (LW) and NingXiang (NX) pigs and further reported m<sup>6</sup>A methylation patterns via MeRIP-seq. We found that m<sup>6</sup>A modification regulates muscle cell development, myofibrils, cell cycle, and phosphatase regulator activity during the neonatal phase of muscle development. Interestingly, differentially expressed genes in LW and NX pigs were mainly enriched in pathways involved in protein synthesis. Furthermore, we performed a conjoint analysis of MeRIP-seq and RNA-seq data and identified 27 differentially expressed and m<sup>6</sup>A-modified genes. Notably, a typical muscle-specific envelope transmembrane protein, WFS1, was differentially regulated by m<sup>6</sup>A modifications in LW and NX pigs. We further revealed that the m<sup>6</sup>A modification accelerated the degradation of WFS1 in a YTHDF2-dependent manner. Noteworthy, we identified a single nucleotide polymorphism (C21551T) within the last exon of WFS1 that resulted in variable m<sup>6</sup>A methylation, contributing to the differing WFS1 expression levels observed in LW and NX pigs. Our study conducted a comprehensive analysis of the m<sup>6</sup>A modification on NX and LW pigs during the neonatal period of muscle development, and elucidated the mechanism by which m<sup>6</sup>A regulates the differential expression of WFS1 in the two breeds.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495925","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}
CellsPub Date : 2024-10-21DOI: 10.3390/cells13201742
Gregor Hoppstock, Jonathan A Lindquist, Antonia Willems, Annika Becker, Charlotte Reichardt, Ronnie Morgenroth, Saskia Stolze, Cheng Zhu, Sabine Brandt, Peter R Mertens
{"title":"DNA-Binding Protein A Is Actively Secreted in a Calcium-and Inflammasome-Dependent Manner and Negatively Influences Tubular Cell Survival.","authors":"Gregor Hoppstock, Jonathan A Lindquist, Antonia Willems, Annika Becker, Charlotte Reichardt, Ronnie Morgenroth, Saskia Stolze, Cheng Zhu, Sabine Brandt, Peter R Mertens","doi":"10.3390/cells13201742","DOIUrl":"https://doi.org/10.3390/cells13201742","url":null,"abstract":"<p><p>DNA-binding protein A (DbpA) belongs to the Y-box family of cold shock domain (CSD) proteins that bind RNA/DNA and exert intracellular functions in cell stress, proliferation, and differentiation. Given the pattern of DbpA staining in inflammatory glomerular diseases, without adherence to cell boundaries, we hypothesized extracellular protein occurrence and specific functions. Lipopolysaccharide and ionomycin induce DbpA expression and secretion from melanoma and mesangial cells. Unlike its homologue Y-box-binding protein 1 (YB-1), DbpA secretion requires inflammasome activation, as secretion is blocked upon the addition of a NOD-like receptor protein-3 (NLRP3) inhibitor. The addition of recombinant DbpA enhances melanoma cell proliferation, migration, and competes with tumor necrosis factor (TNF) binding to its receptor (TNFR1). In TNF-induced cell death assays, rDbpA initially blocks TNF-induced apoptosis, whereas at later time points (>24 h), cells are more prone to die. Given that CSD proteins YB-1 and DbpA fulfill the criteria of alarmins, we propose that their release signals an inherent danger to the host. Some data hint at an extracellular complex formation at a ratio of 10:1 (DbpA:YB-1) of both proteins.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516268","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}
CellsPub Date : 2024-10-20DOI: 10.3390/cells13201739
Elizabeth Skapinker, Emilyn B Aucoin, Haley L Kombargi, Abdulrahman M Yaish, Yunfan Li, Leili Baghaie, Myron R Szewczuk
{"title":"Contemporaneous Inflammatory, Angiogenic, Fibrogenic, and Angiostatic Cytokine Profiles of the Time-to-Tumor Development by Cancer Cells to Orchestrate Tumor Neovascularization, Progression, and Metastasis.","authors":"Elizabeth Skapinker, Emilyn B Aucoin, Haley L Kombargi, Abdulrahman M Yaish, Yunfan Li, Leili Baghaie, Myron R Szewczuk","doi":"10.3390/cells13201739","DOIUrl":"https://doi.org/10.3390/cells13201739","url":null,"abstract":"<p><p>Cytokines can promote various cancer processes, such as angiogenesis, epithelial to mesenchymal transition (EMT), invasion, and tumor progression, and maintain cancer stem-cell-like (CSCs) cells. The mechanism(s) that continuously promote(s) tumors to progress in the TME still need(s) to be investigated. The data in the present study analyzed the inflammatory, angiogenic, fibrogenic, and angiostatic cytokine profiles in the host serum during tumor development in a mouse model of human pancreatic cancer. Pancreatic MiaPaCa-2-eGFP cancer cells were subcutaneously implanted in RAG2xCγ double mutant mice. Blood samples were collected before cancer cell implantation and every week until the end point of the study. The extracted serum from the blood of each mouse at different time points during tumor development was analyzed using a Bio-Plex microarray analysis and a Bio-Plex 200 system for proinflammatory (IL-1β, IL-10, IFN-γ, and TNF-α) and angiogenic and fibrogenic (IL-15, IL-18, basic FGF, LIF, M-CSF, MIG, MIP-2, PDGF-BB, and VEGF) cytokines. Here, we find that during cancer cell colonization for tumor development, host angiogenic, fibrogenic, and proinflammatory cytokine profiling in the tumor-bearing mice has been shown to significantly reduce host angiostatic and proinflammatory cytokines that restrain tumor development and increase those for tumor growth. The proinflammatory cytokines IL-15, IL-18, and IL-1β profiles reveal a significant host serum increase after day 35 when the tumor began to progress in growth. In contrast, the angiostatic cytokine profiles of TNFα, MIG, M-CSF, IL-10, and IFNγ in the host serum revealed a dramatic and significant decrease after day 5 post-implantation of cancer cells. OP treatment of tumor-bearing mice on day 35 maintained high levels of angiostatic and fibrogenic cytokines. The data suggest an entirely new regulation by cancer cells for tumor development. The findings identify for the first time how pancreatic cancer cells use host cytokine profiling to orchestrate the initiation of tumor development.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495935","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}
CellsPub Date : 2024-10-20DOI: 10.3390/cells13201738
Etienne Pays
{"title":"Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease.","authors":"Etienne Pays","doi":"10.3390/cells13201738","DOIUrl":"https://doi.org/10.3390/cells13201738","url":null,"abstract":"<p><p>Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills <i>Trypanosoma brucei</i> through induction of apoptotic-like parasite death, but two <i>T. brucei</i> clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495910","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}
CellsPub Date : 2024-10-20DOI: 10.3390/cells13201740
Samuel L Blount, Xiaochen Liu, Jeffrey D McBride
{"title":"The Utilization of PRAME in the Diagnosis, Prognosis, and Treatment of Melanoma.","authors":"Samuel L Blount, Xiaochen Liu, Jeffrey D McBride","doi":"10.3390/cells13201740","DOIUrl":"https://doi.org/10.3390/cells13201740","url":null,"abstract":"<p><p>Melanoma, a deadly form of skin cancer, has seen improved survival rates due to advances in diagnosis and treatment, yet the need for further improvement remains critical. Tumor-associated antigens, such as PRAME (Preferentially Expressed Antigen in Melanoma), offer promising avenues for enhanced diagnostic precision, prognostic assessment, and targeted immunotherapy. PRAME, a cancer testis antigen, is selectively expressed in various cancers, including melanoma, and plays a key role in promoting tumorigenesis through inhibition of retinoic acid signaling, epithelial-to-mesenchymal transition, and immune evasion. This review explores the diagnostic utility of PRAME in distinguishing melanoma from benign nevi, its prognostic value in aggressive melanoma subtypes, and its potential as a therapeutic target in cancer vaccines and adoptive T-cell therapies. While PRAME-targeted therapies face challenges such as tumor heterogeneity and immune suppression, ongoing research aims to overcome these barriers, offering hope for more effective melanoma treatments.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495969","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":"L-PGDS-PGD2-DP1 Axis Regulates Phagocytosis by CD36<sup>+</sup> MGs/MΦs That Are Exclusively Present Within Ischemic Areas After Stroke.","authors":"Takayuki Nakagomi, Aya Narita, Hideaki Nishie, Akiko Nakano-Doi, Toshinori Sawano, Yu Fukuda, Tomohiro Matsuyama","doi":"10.3390/cells13201737","DOIUrl":"https://doi.org/10.3390/cells13201737","url":null,"abstract":"<p><p>Brain injuries, such as ischemic stroke, cause cell death. Although phagocytosis of cellular debris is mainly performed by microglia/macrophages (MGs/MΦs), excessive accumulation beyond their phagocytic capacities results in waste product buildup, delaying brain cell regeneration. Therefore, it is essential to increase the potential for waste product removal from damaged brains. Lipocalin-type prostaglandin D synthase (L-PGDS) is the primary synthase for prostaglandin D2 (PGD2) and has been reported as a scavenger of waste products. However, the mechanism by which the L-PGDS-PGD2 axis exerts such an effect remains unelucidated. In this study, using a mouse model of ischemic stroke, we found that L-PGDS and its downstream signaling pathway components, including PGD2 and PGD2 receptor DP1 (but not DP2), were significantly upregulated in ischemic areas. Immunohistochemistry revealed the predominant expression of L-PGDS in the leptomeninges of ischemic areas and high expression levels of DP1 in CD36<sup>+</sup> MGs/MΦs that were specifically present within ischemic areas. Furthermore, PGD2 treatment promoted the conversion of MGs/MΦs into CD36<sup>+</sup> scavenger types and increased phagocytic activities of CD36<sup>+</sup> MGs/MΦs. Because CD36<sup>+</sup> MGs/MΦs specifically appeared within ischemic areas after stroke, our findings suggest that the L-PGDS-PGD2-DP1 axis plays an important role in brain tissue repair by regulating phagocytic activities of CD36<sup>+</sup> MGs/MΦs.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495919","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}
CellsPub Date : 2024-10-19DOI: 10.3390/cells13201736
Ramesh Thylur Puttalingaiah, Matthew J Dean, Liqin Zheng, Phaethon Philbrook, Dorota Wyczechowska, Timothy Kayes, Luis Del Valle, Denise Danos, Maria Dulfary Sanchez-Pino
{"title":"Excess Potassium Promotes Autophagy to Maintain the Immunosuppressive Capacity of Myeloid-Derived Suppressor Cells Independent of Arginase 1.","authors":"Ramesh Thylur Puttalingaiah, Matthew J Dean, Liqin Zheng, Phaethon Philbrook, Dorota Wyczechowska, Timothy Kayes, Luis Del Valle, Denise Danos, Maria Dulfary Sanchez-Pino","doi":"10.3390/cells13201736","DOIUrl":"https://doi.org/10.3390/cells13201736","url":null,"abstract":"<p><p>Potassium ions (K<sup>+</sup>) are critical electrolytes that regulate multiple functions in immune cells. Recent studies have shown that the elevated concentration of extracellular potassium in the tumor interstitial fluid limits T cell effector function and suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). The effect of excess potassium on the biology of myeloid-derived suppressor cells (MDSCs), another important immune cell component of the tumor microenvironment (TME), is unknown. Here, we present data showing that increased concentrations of potassium chloride (KCl), as the source of K<sup>+</sup> ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3β. Simultaneously, excess potassium ions significantly decrease the expression of arginase I (Arg I) and inducible nitric oxide synthase (iNOS) without reducing the ability of MDSCs to suppress T cell proliferation. Further investigation reveals that excess K<sup>+</sup> ions decrease the expression of the transcription factor C/EBP-β and alter the expression of phosphorylated kinases. While excess K<sup>+</sup> ions downregulated the expression levels of phospho-AMPKα (pAMPKα), it increased the levels of pAKT and pERK. Additionally, potassium increased mitochondrial respiration as measured by the oxygen consumption rate (OCR). Interestingly, all these alterations induced by K<sup>+</sup> ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K<sup>+</sup> ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs' immunosuppressive function by mechanisms independent of Arg I and iNOS. Overall, our in vitro and ex vivo findings offer valuable insights into the adaptations of MDSCs within the K<sup>+</sup> ion-rich TME, which has important implications for MDSCs-targeted therapies.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495957","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}