{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T18:29:04Z","timestamp":1785608944049,"version":"3.56.0"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2011,5,1]],"date-time":"2011-05-01T00:00:00Z","timestamp":1304208000000},"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":["Infect Immun"],"published-print":{"date-parts":[[2011,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The immune response to<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cryptococcus neoformans<\/jats:named-content>following pulmonary infection of C57BL\/6 wild-type (WT) mice results in the development of persistent infection with characteristics of allergic bronchopulmonary mycosis (ABPM). To further clarify the role of Th1\/Th2 polarizing cytokines in this model, we performed kinetic analysis of cytokine responses and compared cytokine profiles, pathologies, and macrophage (Mac) polarization status in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. neoformans<\/jats:named-content>-infected WT, interleukin-4-deficient (IL-4<jats:sup>\u2212\/\u2212<\/jats:sup>), and gamma interferon-deficient (IFN-\u03b3<jats:sup>\u2212\/\u2212<\/jats:sup>) C57BL\/6 mice. Results show that cytokine expression in the infected WT mice is not permanently Th2 biased but changes dynamically over time. Using multiple Mac activation markers, we further demonstrate that IL-4 and IFN-\u03b3 regulate the polarization state of Macs in this model. A higher IL-4\/IFN-\u03b3 ratio leads to the development of alternatively activated Macs (aaMacs), whereas a higher IFN-\u03b3\/IL-4 ratio leads to the generation of classically activated Macs (caMacs). WT mice that coexpress IL-4 and IFN-\u03b3 during fungal infection concurrently display both types of Mac polarization markers. Concurrent stimulation of Macs with IFN-\u03b3 and IL-4 results in an upregulation of both sets of markers within the same cells, i.e., formation of an intermediate aaMac\/caMac phenotype. These cells express both inducible nitric oxide synthase (important for clearance) and arginase (associated with chronic\/progressive infection). Together, our data demonstrate that the interplay between Th1 and Th2 cytokines supports chronic infection, chronic inflammation, and the development of ABPM pathology in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. neoformans<\/jats:named-content>-infected lungs. This cytokine interplay modulates Mac differentiation, including generation of an intermediate caMac\/aaMac phenotype, which in turn may support chronic \u201csteady-state\u201d fungal infection and the resultant ABPM pathology.<\/jats:p>","DOI":"10.1128\/iai.01270-10","type":"journal-article","created":{"date-parts":[[2011,3,8]],"date-time":"2011-03-08T06:53:58Z","timestamp":1299567238000},"page":"1915-1926","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":123,"title":["Effect of Cytokine Interplay on Macrophage Polarization during Chronic Pulmonary Infection with Cryptococcus neoformans"],"prefix":"10.1128","volume":"79","author":[{"given":"Shikha","family":"Arora","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"},{"name":"Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"},{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal A.","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"},{"name":"Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"},{"name":"VA Ann Arbor Health System, Ann Arbor, Michigan 48105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany M.","family":"Tsang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"},{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick A.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galen B.","family":"Toews","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"},{"name":"VA Ann Arbor Health System, Ann Arbor, Michigan 48105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary B.","family":"Huffnagle","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"},{"name":"Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"},{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0642"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.59.7.2291-2296.1991"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6346"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.8.5545"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01489-07"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6095"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01143-07"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.060595"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/653829"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425640"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1671"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/3327"},{"key":"e_1_3_2_13_2","first-page":"1275","article-title":"Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus neoformans granulomas","volume":"148","author":"Goldman D.","year":"1996","unstructured":"GoldmanD.ChoY.ZhaoM.CasadevallA.LeeS. 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