title: NFATc1 releases BCL6-dependent repression of CCR2 agonist expression in peritoneal macrophages from Saccharomyces cerevisiae infected mice.
abstract: The link between the extensive usage of calcineurin (CN) inhibitors cyclosporin A and tacrolimus (FK506) in transplantation medicine and the increasing rate of opportunistic infections within this segment of patients is alarming. Currently, how peritoneal infections are favored by these drugs, which impair the activity of several signaling pathways including the Ca(++) /CN/NFAT, Ca(++) /CN/cofilin, Ca(++) /CN/BAD, and NF-κB networks, is unknown. Here, we show that Saccharomyces cerevisiae infection of peritoneal resident macrophages triggers the transient nuclear translocation of NFATc1β isoforms, resulting in a coordinated, CN-dependent induction of the Ccl2, Ccl7, and Ccl12 genes, all encoding CCR2 agonists. CN inhibitors block the CCR2-dependent recruitment of inflammatory monocytes (IM) to the peritoneal cavities of S. cerevisiae infected mice. In myeloid cells, NFATc1/β proteins represent the most prominent NFATc1 isoforms. NFATc1/β ablation leads to a decrease of CCR2 chemokines, impaired mobilization of IMs, and delayed clearance of infection. We show that, upon binding to a composite NFAT/BCL6 regulatory element within the Ccl2 promoter, NFATc1/β proteins release the BCL6-dependent repression of Ccl2 gene in macrophages. These findings suggest a novel CN-dependent cross-talk between NFAT and BCL6 transcription factors, which may affect the outcome of opportunistic fungal infections in immunocompromised patients.
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Rhoda
authors.initials: R
authors.lastname: Busch
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Krisna
authors.initials: K
authors.lastname: Murti
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Jiming
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Amiya K
authors.initials: AK
authors.lastname: Patra
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Khalid
authors.initials: K
authors.lastname: Muhammad
authors.affiliation: Institute of Neuropathology, University Clinic Freiburg, Freiburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.affiliation: School of Cancer Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Lichtinger
authors.affiliation: School of Cancer Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
authors.affiliation: Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Wörtge
authors.affiliation: Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Reifenberg
authors.affiliation: Clinic of Gastroenterology and Gastrointestinal Oncology, University of Goettingen, Goettingen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Ellenrieder
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Serfling
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Andris
authors.initials: A
authors.lastname: Avots
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D018932:Chemokine CCL2 / Q000235:genetics; D054410:Chemokine CCL7 / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics; D009000:Monocytes / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D009894:Opportunistic Infections / Q000276:immunology / Q000821:virology; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D021381:Protein Transport; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000819:agonists* / Q000276:immunology*; D012441:Saccharomyces cerevisiae / Q000276:immunology*
chemical_list: D065095:Calcineurin Inhibitors; C491224:Ccl12 protein, mouse; C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D018945:Monocyte Chemoattractant Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D020033:Protein Isoforms; D051560:Proto-Oncogene Proteins c-bcl-6; D054390:Receptors, CCR2; D019703:Calcineurin
keywords: BCL6; CCL2; CCR2; Inflammatory monocytes; NFATc1; Opportunistic infection