{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T19:09:40Z","timestamp":1793905780309,"version":"4.8.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Objectives<\/jats:title>\n \n The mechanism of Brucella infection regulating macrophage phenotype has not been completely elucidated until now. This study aimed to determine the mechanism of\n Brucella abortus<\/jats:italic>\n in the modulation of macrophage phenotype using RAW264.7 cells as a model.\n <\/jats:p>\n <\/jats:sec>\n \n Materials and methods<\/jats:title>\n \n RT-qPCR, ELISA and flow cytometry were used to detect the inflammatory factor production and phenotype conversion associated with M1\/M2 polarization of macrophages by\n Brucella abortus<\/jats:italic>\n infection. Western blot and immunofluorescence were used to analyze the role of nuclear factor kappa B (NF-\u03baB) signaling pathway in regulation of\n Brucella abortus<\/jats:italic>\n -induced macrophage polarization. Chromatin immunoprecipitation sequencing (Chip\u2010seq), bioinformatics analysis and luciferase reporter assay were used to screen and validate NF-\u03baB target genes associated with macrophage polarization and further verify its function.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The results demonstrate that\n B. abortus<\/jats:italic>\n induces a macrophage phenotypic switch and inflammatory response in a time-dependent manner.\n With the increase of infection time<\/jats:italic>\n ,\n B. abortus<\/jats:italic>\n infection-induced M1-type increased first, peaked at 12\u00a0h, and then decreased, whereas the M2-type decreased first, trough at 12\u00a0h, and then increased. The trend of intracellular survival of\n B. abortus<\/jats:italic>\n was consistent with that of M2 type. When NF-\u03baB was inhibited, M1-type polarization was inhibited and M2-type was promoted, and the intracellular survival of\n B. abortus<\/jats:italic>\n increased significantly. Chip\u2010seq and luciferase reporter assay results showed that NF-\u03baB binds to the glutaminase gene (\n Gls<\/jats:italic>\n ).\n Gls<\/jats:italic>\n expression was down-regulated when NF-\u03baB was inhibited. Furthermore, when\n Gls<\/jats:italic>\n was inhibited, M1-type polarization was inhibited and M2-type was promoted, the intracellular survival of\n B. abortus<\/jats:italic>\n increased significantly. Our data further suggest that NF-\u03baB and its key target gene\n Gls<\/jats:italic>\n play an important role in controlling macrophage phenotypic transformation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Taken together, our study demonstrates that\n B. abortus<\/jats:italic>\n infection can induce dynamic transformation of M1\/M2 phenotype in macrophages. Highlighting NF-\u03baB as a central pathway that regulates M1\/M2 phenotypic transition. This is the first to elucidate the molecular mechanism of\n B. abortus<\/jats:italic>\n regulation of macrophage phenotype switch and inflammatory response by regulating the key gene\n Gls<\/jats:italic>\n , which is regulated by the transcription factor NF-\u03baB.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2023.1180837","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T01:27:59Z","timestamp":1685496479000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Brucella abortus modulates macrophage polarization and inflammatory response by targeting glutaminases through the NF-\u03baB signaling pathway"],"prefix":"10.3389","volume":"14","author":[{"given":"Tianyi","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zedan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangbo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingmei","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dexin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuzhu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjin","family":"Chai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Usevich Vera","family":"Nikolaevna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suleimenov","family":"Maratbek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1080\/01652176.2020.1868616","article-title":"Bovine brucellosis - a comprehensive review","volume":"41","author":"Khurana","year":"2021","journal-title":"Vet Q"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2020.117280","article-title":"Brucellosis","volume":"420","author":"Shakir","year":"2021","journal-title":"J Neurol Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009597","article-title":"STING regulates metabolic reprogramming in macrophages via HIF-1\u03b1 during brucella infection","volume":"17","author":"Gomes","year":"2021","journal-title":"PLoS Pathog"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms10102003","article-title":"Brucella phagocytosis mediated by pathogen-host interactions and their intracellular survival","volume":"10","author":"Huy","year":"2022","journal-title":"Microorganisms"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00691","article-title":"Brucella dysregulates monocytes and inhibits macrophage polarization through LC3-dependent autophagy","volume":"8","author":"Wang","year":"2017","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.rvsc.2022.02.006","article-title":"Brucella induces M1 to M2 polarization of macrophages through STAT6 signaling pathway to promote bacterial intracellular survival","volume":"145","author":"Wang","year":"2022","journal-title":"Res Vet Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01902","article-title":"Infection of mycobacterium tuberculosis promotes both M1\/M2 polarization and MMP production in cigarette smoke-exposed macrophages","volume":"11","author":"Le","year":"2020","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1158\/1538-7445.SABCS19-BS1-2","article-title":"Pancreatic cancer-derived small extracellular vesical ezrin regulates macrophage polarization and promotes metastasis","volume":"10","author":"Chang","year":"2020","journal-title":"Am J Cancer Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.121137","article-title":"M1 macrophage exosomes engineered to foster M1 polarization and target the IL-4 receptor inhibit tumor growth by reprogramming tumor-associated macrophages into M1-like macrophages","volume":"278","author":"Gunassekaran","year":"2021","journal-title":"Biomaterials"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2020.173090","article-title":"Macrophage M1\/M2 polarization","volume":"877","author":"Yunna","year":"2020","journal-title":"Eur J Pharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00614","article-title":"Molecular mechanisms that influence the macrophage M1\u2013M2 polarization balance","volume":"5","author":"Wang","year":"2014","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040938","article-title":"Interleukin 26 skews macrophage polarization towards M1 phenotype by activating cJUN and the NF-\u03baB pathway","volume":"9","author":"Lin","year":"2020","journal-title":"Cells"},{"key":"B13","doi-asserted-by":"publisher","first-page":"4353","DOI":"10.1038\/s41467-019-12384-2","article-title":"Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24","volume":"10","author":"Yu","year":"2019","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s12865-020-00355-y","article-title":"Progranulin inhibits LPS-induced macrophage M1 polarization via NF-\u043aB and MAPK pathways","volume":"21","author":"Liu","year":"2020","journal-title":"BMC Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1007\/s10753-018-0753-3","article-title":"Nobiletin-ameliorated lipopolysaccharide-induced inflammation in acute lung injury by suppression of NF-kappa b pathway In vivo and vitro","volume":"41","author":"Zhao","year":"2018","journal-title":"Inflamm"},{"key":"B16","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.molimm.2017.06.019","article-title":"Nicorandil modulated macrophages activation and polarization via NF-\u03bab signaling pathway","volume":"88","author":"Zhang","year":"2017","journal-title":"Mol Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-022-00841-w","article-title":"MEF2C promotes M1 macrophage polarization and Th1 responses","volume":"19","author":"Zhao","year":"2022","journal-title":"Cell Mol Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1080\/20002297.2020.1868152","article-title":"Enterococcus faecalis shifts macrophage polarization toward M1-like phenotype with an altered cytokine profile","volume":"13","author":"Elashiry","year":"2021","journal-title":"J Oral Microbiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.02447","article-title":"PGE2 augments inflammasome activation and M1 polarization in macrophages infected with salmonella typhimurium and yersinia enterocolitica","volume":"9","author":"Sheppe","year":"2018","journal-title":"Front Microbiol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143593","article-title":"M2 polarization of human macrophages favors survival of the intracellular pathogen chlamydia pneumoniae","volume":"10","author":"Buchacher","year":"2015","journal-title":"PLoS One"},{"key":"B21","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.chom.2019.11.011","article-title":"Salmonella-driven polarization of granuloma macrophages antagonizes TNF-mediated pathogen restriction during persistent infection","volume":"27","author":"Pham","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02550-18","article-title":"Biphasic dynamics of macrophage immunometabolism during mycobacterium tuberculosis infection","volume":"10","author":"Shi","year":"2019","journal-title":"mBio"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01175","article-title":"Transcriptional regulation of macrophages polarization by MicroRNAs","volume":"9","author":"Li","year":"2018","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22189754","article-title":"Dehydrocostus lactone attenuates methicillin-resistant staphylococcus aureus-induced inflammation and acute lung injury via modulating macrophage polarization","volume":"22","author":"Wu","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.14781","article-title":"Negative pressure promotes macrophage M1 polarization after mycobacterium tuberculosis infection via the lncRNA XIST\/microRNA-125b-5p\/A20\/NF-\u03baB axis","volume":"1514","author":"Luo","year":"2022","journal-title":"Ann N Y Acad Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1183621","article-title":"Variation in transcription factor binding among humans","volume":"328","author":"Kasowski","year":"2010","journal-title":"Science"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/jobm.201900458","article-title":"ChIP-seq analysis of brucella reveals transcriptional regulation of GntR","volume":"60","author":"Li","year":"2020","journal-title":"J Basic Microbiol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for illumina sequence data","volume":"15","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2164-8-246","article-title":"EasyGO: gene ontology-based annotation and functional enrichment analysis tool for agronomical species","volume":"8","author":"Zhen","year":"2007","journal-title":"BMC Genomics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-6-60","article-title":"PathwayVoyager: pathway mapping using the Kyoto encyclopedia of genes and genomes (KEGG) database","volume":"6","author":"Altermann","year":"2005","journal-title":"BMC Genomics"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an r package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01084","article-title":"Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages","volume":"10","author":"Orecchioni","year":"2019","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e328344b73e","article-title":"Macrophage polarization and bacterial infections","volume":"24","author":"M\u00e8ge","year":"2011","journal-title":"Curr Opin Infect Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073673","article-title":"The mechanism of facultative intracellular parasitism of brucella","volume":"22","author":"Jiao","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s12866-018-1185-9","article-title":"Heat-stress-modulated induction of NF-\u03baB leads to brucellacidal pro-inflammatory defense against brucella abortus infection in murine macrophages and in a mouse model","volume":"18","author":"Hop","year":"2018","journal-title":"BMC Microbiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14779","article-title":"Four transcription profile\u2013based models identify novel prognostic signatures in oesophageal cancer","volume":"24","author":"Liu","year":"2019","journal-title":"J Cell Mol Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101302","article-title":"Natural product celastrol suppressed macrophage M1 polarization against inflammation in diet-induced obese mice via regulating Nrf2\/HO-1, MAP kinase and NF-\u03baB pathways","volume":"9","author":"Luo","year":"2017","journal-title":"Aging (Albany NY)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.01.020","article-title":"Shared principles in NF-kappaB signaling","volume":"132","author":"Hayden","year":"2008","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01274-22","article-title":"Glutamine is required for M1-like polarization of macrophages in response to mycobacterium tuberculosis infection","volume":"13","author":"Jiang","year":"2022","journal-title":"mBio"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/nu8040215","article-title":"Glutamine modulates macrophage lipotoxicity","volume":"8","author":"He","year":"2016","journal-title":"Nutrients"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3796","article-title":"\u03b1-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming","volume":"18","author":"Liu","year":"2017","journal-title":"Nat Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.02.005","article-title":"Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization","volume":"42","author":"Jha","year":"2015","journal-title":"Immunity"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01462","article-title":"The metabolic signature of macrophage responses","volume":"10","author":"Viola","year":"2019","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-08-520619","article-title":"Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct","volume":"123","author":"Gundra","year":"2014","journal-title":"Blood"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.001","article-title":"Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism","volume":"175","author":"Johnson","year":"2018","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901610","article-title":"Blockade of lncRNA-ASLNCS5088\u2013enriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation","volume":"33","author":"Chen","year":"2019","journal-title":"FASEB J"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens9121008","article-title":"ASC-mediated inflammation and pyroptosis attenuates brucella abortus pathogenesis following the recognition of gDNA","volume":"9","author":"Tupik","year":"2020","journal-title":"Pathogens"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1180837\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T01:28:03Z","timestamp":1685496483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1180837\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,31]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2023.1180837"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1180837","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,31]]},"article-number":"1180837"}}