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: Gisa Ellrichmann, Jan Thöne, De-Hyung Lee, Rudolph A Rupec, Ralf Gold, Ralf A Linker
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 9 Pg. 15 (Jan 20 2012) ISSN: 1742-2094 [Electronic] England
• PMID: 22260436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD11b Antigen
• Cytokines
• Glycoproteins
• I kappa B beta protein
• I-kappa B Proteins
• Myelin-Oligodendrocyte Glycoprotein
• Peptide Fragments
• myelin oligodendrocyte glycoprotein (35-55)
• Nitric Oxide Synthase Type II

Topics

• Animals
• CD11b Antigen (metabolism)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cytokines (metabolism)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, pathology)
• Enzyme-Linked Immunosorbent Assay (methods)
• Flow Cytometry
• Glycoproteins (adverse effects)
• I-kappa B Proteins (deficiency, metabolism)
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Monocytes (metabolism)
• Myelin-Oligodendrocyte Glycoprotein
• Neutrophil Infiltration (drug effects, immunology)
• Nitric Oxide Synthase Type II (metabolism)
• Peptide Fragments (adverse effects)
• Spleen (cytology)