{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:20:17Z","timestamp":1789086017441,"version":"build-2803163510"},"reference-count":68,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T00:00:00Z","timestamp":1729296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["P20CA233374"],"award-info":[{"award-number":["P20CA233374"]}]},{"name":"National Institutes of Health","award":["U54-GM104940"],"award-info":[{"award-number":["U54-GM104940"]}]},{"DOI":"10.13039\/100018106","name":"Louisiana Clinical and Translational Science Center","doi-asserted-by":"publisher","award":["P20CA233374"],"award-info":[{"award-number":["P20CA233374"]}],"id":[{"id":"10.13039\/100018106","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018106","name":"Louisiana Clinical and Translational Science Center","doi-asserted-by":"publisher","award":["U54-GM104940"],"award-info":[{"award-number":["U54-GM104940"]}],"id":[{"id":"10.13039\/100018106","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Potassium ions (K+) 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+ ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3\u03b2. 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+ ions decrease the expression of the transcription factor C\/EBP-\u03b2 and alter the expression of phosphorylated kinases. While excess K+ ions downregulated the expression levels of phospho-AMPK\u03b1 (pAMPK\u03b1), 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+ ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K+ ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs\u2019 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+ ion-rich TME, which has important implications for MDSCs-targeted therapies.<\/jats:p>","DOI":"10.3390\/cells13201736","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T03:57:09Z","timestamp":1729483029000},"page":"1736","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Excess Potassium Promotes Autophagy to Maintain the Immunosuppressive Capacity of Myeloid-Derived Suppressor Cells Independent of Arginase 1"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8935-6780","authenticated-orcid":false,"given":"Ramesh","family":"Thylur Puttalingaiah","sequence":"first","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Dean","sequence":"additional","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4927-8092","authenticated-orcid":false,"given":"Phaethon","family":"Philbrook","sequence":"additional","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8940-6861","authenticated-orcid":false,"given":"Dorota","family":"Wyczechowska","sequence":"additional","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Kayes","sequence":"additional","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3894-9206","authenticated-orcid":false,"given":"Luis","family":"Del Valle","sequence":"additional","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Danos","sequence":"additional","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5271-9840","authenticated-orcid":false,"given":"Maria Dulfary","family":"Sanchez-Pino","sequence":"additional","affiliation":[{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.4103\/ijcep.ijcep_43_17","article-title":"Potassium Homeostasis, Oxidative Stress, and Human Disease","volume":"4","author":"Udensi","year":"2017","journal-title":"Int. J. Clin. Exp. 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