title: IκBNS regulates murine Th17 differentiation during gut inflammation and infection.
abstract: IL-17-producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A-producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS (-/-) Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS (-/-) mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections.
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Institute for Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany;
authors.forename: Michaela
authors.initials: M
authors.lastname: Annemann
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany; and.
authors.forename: Zuobai
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Institute for Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany;
authors.forename: Carlos
authors.initials: C
authors.lastname: Plaza-Sirvent
authors.affiliation: Medizinische Klinik I, Charité - Universitätsmedizin Berlin, 12203 Berlin, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Glauben
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Institute for Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany;
authors.forename: Marc
authors.initials: M
authors.lastname: Schuster
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Institute for Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany;
authors.forename: Frida
authors.initials: F
authors.lastname: Ewald Sander
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany; and.
authors.forename: Panagiota
authors.initials: P
authors.lastname: Mamareli
authors.affiliation: Medizinische Klinik I, Charité - Universitätsmedizin Berlin, 12203 Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Medizinische Klinik I, Charité - Universitätsmedizin Berlin, 12203 Berlin, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany; and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lochner
authors.affiliation: Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Institute for Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany; ingo.schmitz@helmholtz-hzi.de.
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics; D044082:Citrobacter rodentium / Q000276:immunology* / Q000502:physiology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000276:immunology; D020672:I-kappa B Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B