{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:03:58Z","timestamp":1792674238050,"version":"4.5.0"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2013,6,18]],"date-time":"2013-06-18T00:00:00Z","timestamp":1371513600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2013,7,1]],"date-time":"2013-07-01T00:00:00Z","timestamp":1372636800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The outcome of cryptococcal pneumonia correlates with local macrophage polarization status, as M1 and M2 polarization marks protective and nonprotective responses, respectively. Overall, pulmonary macrophage polarization status changes over time during a cryptococcal infection. This could have been caused by repolarization of individual macrophages or by a replacement of M2-polarized cells by new M1-polarized cells. To explore the ability of macrophages to change between polarization states, we conducted a series of experiments using\n                    <jats:italic>in vitro<\/jats:italic>\n                    macrophages. Coculture of macrophages with\n                    <jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>\n                    resulted in development of a weak M1-like phenotype, with modestly increased inducible nitric oxide synthase (iNOS) but lacking interleukin 6 (IL-6) induction. The\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    -induced M1-like polarization state was plastic, as macrophages stimulated first with\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    and then with gamma interferon (IFN-\u03b3) or IL-4 expressed mRNA polarization patterns similar to those stimulated with cytokines alone. To further evaluate macrophage polarization plasticity, cytokine stimulatory conditions were established which fully polarized macrophages. IFN-\u03b3 and IL-4 stimulation differentially induced complete M1 and M2 polarization, defined by differential expression of marker mRNA panels, surface marker expression, and tumor necrosis factor alpha (TNF-\u03b1) protein production. Switching IFN-\u03b3- to IL-4-stimulating conditions, and vice versa, resulted in uniform changes in profiles of polarization marker genes consistent with the most recent cytokine environment. Furthermore, the ability of sequentially stimulated macrophages to inhibit\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    reflected the most recent polarizing condition, independent of previous polarization. Collectively, these data indicate that M1\/M2 macrophage polarization phenotypes are highly plastic to external signals, and interventions which therapeutically repolarize macrophages could be beneficial for treatment of cryptococcosis.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Our studies reveal how a major opportunistic fungal pathogen,\n                    <jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>\n                    , interacts with macrophages, immune cells which can ingest and kill invading pathogens. Macrophages play a crucial role in the pathogenesis of cryptococcal infection, as their polarization phenotype determines the outcome of the battle between the infected host and\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    . This study suggests that dynamic changes in polarization of macrophages at the level of individual cells are an important characteristic of\n                    <jats:italic>in vivo<\/jats:italic>\n                    cryptococcosis, as they occur throughout the natural course of infection. We demonstrate that macrophages can rapidly and uniformly reverse their polarization phenotype in response to dynamic signaling conditions and lose or regain their fungicidal function. Demonstrating importance of these pathways may become a cornerstone for novel therapeutic strategies for treatment of cryptococcosis in both immunocompromised and immunocompetent patients.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00264-13","type":"journal-article","created":{"date-parts":[[2013,6,18]],"date-time":"2013-06-18T22:42:25Z","timestamp":1371595345000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":390,"title":["Macrophage M1\/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in Cryptococcus neoformans Infection"],"prefix":"10.1128","volume":"4","author":[{"given":"Michael J.","family":"Davis","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany M.","family":"Tsang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Department of Molecular, Cellular and Developmental Biology, Yale University, Kline Biology Tower, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafeng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy K.","family":"Dayrit","sequence":"additional","affiliation":[{"name":"Veterans Affairs, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joudeh B.","family":"Freij","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary B.","family":"Huffnagle","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal A.","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Veterans Affairs, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198909213211205"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e3282a4a64d"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e328322ffac"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-008-0529-z"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0242-6498(04)93945-4"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1405.071312"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6346"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090634"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.090530"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2010.11.006"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.06.012"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.323"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R700045200"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI113427"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.59.7.2291-2296.1991"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(04)00107-4"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1451"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080673"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00297-09"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.05.007"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59643"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.8.5367"},{"key":"e_1_3_2_24_2","doi-asserted-by":"crossref","unstructured":"NicolaAM RobertsonEJ AlbuquerqueP DerengowskiLda S CasadevallA . 2011. 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