{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T21:00:49Z","timestamp":1780520449420,"version":"3.54.1"},"reference-count":52,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T00:00:00Z","timestamp":1681430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"INFECT-ERA grant of the European Union","award":["FWF-I03321"],"award-info":[{"award-number":["FWF-I03321"]}]},{"name":"INFECT-ERA grant of the European Union","award":["W1253"],"award-info":[{"award-number":["W1253"]}]},{"name":"Austrian Research Funds","award":["FWF-I03321"],"award-info":[{"award-number":["FWF-I03321"]}]},{"name":"Austrian Research Funds","award":["W1253"],"award-info":[{"award-number":["W1253"]}]},{"name":"FWF-Doc-Funds Project-82","award":["FWF-I03321"],"award-info":[{"award-number":["FWF-I03321"]}]},{"name":"FWF-Doc-Funds Project-82","award":["W1253"],"award-info":[{"award-number":["W1253"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Priming of macrophages with interferon-gamma (IFN\u03b3) or interleukin-4 (IL-4) leads to polarisation into pro-inflammatory or anti-inflammatory subtypes, which produce key enzymes such as inducible nitric oxide synthase (iNOS) and arginase 1 (ARG1), respectively, and in this way determine host responses to infection. Importantly, L-arginine is the substrate for both enzymes. ARG1 upregulation is associated with increased pathogen load in different infection models. However, while differentiation of macrophages with IL-4 impairs host resistance to the intracellular bacterium Salmonella enterica serovar Typhimurium (S.tm), little is known on the effects of IL-4 on unpolarised macrophages during infection. Therefore, bone-marrow-derived macrophages (BMDM) from C57BL\/6N, Tie2Cre+\/\u2212ARG1fl\/fl (KO), Tie2Cre\u2212\/\u2212ARG1fl\/fl (WT) mice were infected with S.tm in the undifferentiated state and then stimulated with IL-4 or IFN\u03b3. In addition, BMDM of C57BL\/6N mice were first polarised upon stimulation with IL-4 or IFN\u03b3 and then infected with S.tm. Interestingly, in contrast to polarisation of BMDM with IL-4 prior to infection, treatment of non-polarised S.tm-infected BMDM with IL-4 resulted in improved infection control whereas stimulation with IFN\u03b3 led to an increase in intracellular bacterial numbers compared to unstimulated controls. This effect of IL-4 was paralleled by decreased ARG1 levels and increased iNOS expression. Furthermore, the L-arginine pathway metabolites ornithine and polyamines were enriched in unpolarised cells infected with S.tm and stimulated with IL-4. Depletion of L-arginine reversed the protective effect of IL-4 toward infection control. Our data show that stimulation of S.tm-infected macrophages with IL-4 reduced bacterial multiplication via metabolic re-programming of L-arginine-dependent pathways.<\/jats:p>","DOI":"10.3390\/cells12081164","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T10:29:16Z","timestamp":1681468156000},"page":"1164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Timing of Interleukin-4 Stimulation of Macrophages Determines Their Anti-Microbial Activity during Infection with Salmonella\u00a0enterica Serovar Typhimurium"],"prefix":"10.3390","volume":"12","author":[{"given":"Natascha","family":"Brigo","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emely","family":"Neumaier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa","family":"Pfeifhofer-Obermair","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6233-8910","authenticated-orcid":false,"given":"Philipp","family":"Grubwieser","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Engl","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Seifert","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"},{"name":"Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3706-2910","authenticated-orcid":false,"given":"Vera","family":"Reinstadler","sequence":"additional","affiliation":[{"name":"Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Muellerstrasse 44, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0963-8268","authenticated-orcid":false,"given":"Herbert","family":"Oberacher","sequence":"additional","affiliation":[{"name":"Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Muellerstrasse 44, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0709-2158","authenticated-orcid":false,"given":"G\u00fcnter","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"},{"name":"Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1126\/science.aai8132","article-title":"Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells","volume":"356","author":"Bosurgi","year":"2017","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s00424-017-1944-8","article-title":"\u201cPumping iron\u201d-how macrophages handle iron at the systemic, microenvironmental, and cellular levels","volume":"469","author":"Nairz","year":"2017","journal-title":"Pflug. 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