title: Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation.
abstract: The NF-κB/REL-family of transcription factors plays a central role in coordinating the expression of a wide variety of genes controlling immune responses including autoimmunity of the central nervous system (CNS). The inactive form of NF-κB consists of a heterodimer which is complexed with its inhibitor, IκB. Conditional knockout-mice for IκBα in myeloid cells (lysMCreIκBα(fl/fl)) have been generated and are characterized by a constitutive activation of NF-κB proteins allowing the study of this transcription factor in myelin-oligodendrocyte-glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE), a well established experimental model for autoimmune demyelination of the CNS.In comparison to controls, lysMCreIκBα(fl/fl) mice developed a more severe clinical course of EAE. Upon histological analysis on day 15 p.i., there was an over two fold increased infiltration of T-cells and macrophages/microglia. In addition, lysMCreIκBα(fl/fl) mice displayed an increased expression of the NF-κB dependent factor inducible nitric oxide synthase in inflamed lesions. These changes in the CNS are associated with increased numbers of CD11b positive splenocytes and a higher expression of Ly6c on monocytes in the periphery. Well in accordance with these changes in the myeloid cell compartment, there was an increased production of the monocyte cytokines interleukin(IL)-12 p70, IL-6 and IL-1beta in splenocytes. In contrast, production of the T-cell associated cytokines interferon gamma (IFN-gamma) and IL-17 was not influenced.In summary, myeloid cell derived NF-κB plays a crucial role in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and macrophages independently from T-cells.
authors.affiliation: Department of Neurology, St Josef Hospital Bochum, Ruhr-University Bochum, Germany.
authors.forename: Gisa
authors.initials: G
authors.lastname: Ellrichmann
authors.forename: Jan
authors.initials: J
authors.lastname: Thöne
authors.forename: De-Hyung
authors.initials: DH
authors.lastname: Lee
authors.forename: Rudolph A
authors.initials: RA
authors.lastname: Rupec
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Linker
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry; D006023:Glycoproteins / Q000009:adverse effects; D020672:I-kappa B Proteins / Q000172:deficiency / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010446:Peptide Fragments / Q000009:adverse effects; D013154:Spleen / Q000166:cytology
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D006023:Glycoproteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D052247:Nitric Oxide Synthase Type II