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Various ion channels expressed in macrophages have been documented, but very little is known about their roles in macrophage polarization. We found that knockdown or blockade of the Kir2.1 (also known as KCNJ2) channel significantly inhibited M1 macrophage polarization, but promoted M2 macrophage polarization. Lipopolysaccharide (LPS)-induced M1 polarization was also remarkably suppressed in high extracellular K+ solutions (70\u2005mM K+), and this inhibition was partially abolished by adding Ca2+ to the culture medium. Ca2+ imaging showed that Ca2+ influx was dependent on the hyperpolarized membrane potential generated by the Kir2.1 channel. The upregulation of phospho (p)-CaMK II, p-ERK, and p-NF-\u03baB proteins in macrophages from the RAW264.7 cell line that were stimulated with LPS was significantly reversed by blocking the Kir2.1 channel or culturing the cells with 70\u2005mM K+ medium. Furthermore, in vivo studies showed that mice treated with a Kir2.1 channel blocker were protected from LPS-induced peritonitis. In summary, our data reveal the essential role of the Kir2.1 channel in regulating macrophage polarization via the Ca2+\/CaMK II\/ERK\/NF-\u03baB signaling pathway.<\/jats:p>","DOI":"10.1242\/jcs.259544","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T08:37:54Z","timestamp":1655109474000},"source":"Crossref","is-referenced-by-count":27,"title":["Kir2.1 channel regulates macrophage polarization via the Ca2+\/CaMK II\/ERK\/NF-\u03baB signaling pathway"],"prefix":"10.1242","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-1229","authenticated-orcid":false,"given":"Kuihao","family":"Chen","sequence":"first","affiliation":[{"name":"The Affiliated Hospital of Medical School of Ningbo University 1 Department of Cardiology , , 247 Renmin Road, Ningbo, 315000 , China"},{"name":"Ningbo University School of Medicine 2 Department of Pharmacology , , 818 Fenghua Road, Ningbo, 315000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6491-4536","authenticated-orcid":false,"given":"Qiaoyan","family":"Man","sequence":"additional","affiliation":[{"name":"Ningbo University School of Medicine 2 Department of Pharmacology , , 818 Fenghua Road, Ningbo, 315000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5109-3882","authenticated-orcid":false,"given":"Jiaen","family":"Miao","sequence":"additional","affiliation":[{"name":"Ningbo University School of Medicine 2 Department of Pharmacology , , 818 Fenghua Road, Ningbo, 315000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6354-7420","authenticated-orcid":false,"given":"Wenjing","family":"Xu","sequence":"additional","affiliation":[{"name":"Ningbo University School of Medicine 2 Department of Pharmacology , , 818 Fenghua Road, Ningbo, 315000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7435-0121","authenticated-orcid":false,"given":"Yangchen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Ningbo University School of Medicine 2 Department of Pharmacology , , 818 Fenghua Road, Ningbo, 315000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8243-9003","authenticated-orcid":false,"given":"Xiuli","family":"Zhou","sequence":"additional","affiliation":[{"name":"Ningbo University School of Medicine 2 Department of Pharmacology , , 818 Fenghua Road, Ningbo, 315000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6968-9737","authenticated-orcid":false,"given":"Zhe","family":"Gao","sequence":"additional","affiliation":[{"name":"The Affiliated Hospital of Medical School of Ningbo University 1 Department of Cardiology , , 247 Renmin Road, Ningbo, 315000 , China"},{"name":"Ningbo Institute of Medical Sciences 3 , 42 Yangshan Road, Ningbo, 315000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"2022070811033858900_JCS259544C1","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1038\/ni.1937","article-title":"Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm","volume":"11","author":"Biswas","year":"2010","journal-title":"Nat. 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