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Open Access Highly Accessed Research

Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation

Gisa Ellrichmann1, Jan Thöne1, De-Hyung Lee13, Rudolph A Rupec2, Ralf Gold1 and Ralf A Linker13*

Author Affiliations

1 Department of Neurology, St. Josef Hospital Bochum, Ruhr-University Bochum, Germany

2 Department of Dermatology, Ludwig-Maximilian-University Munich, Germany

3 Department of Neurology, Friedrich-Alexander-University Erlangen, Germany

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Journal of Neuroinflammation 2012, 9:15  doi:10.1186/1742-2094-9-15

Published: 20 January 2012

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 (lysMCreIκBαfl/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, lysMCreIκBαfl/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, lysMCreIκBαfl/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.

Keywords:
NF-kappaB; myeloid cells; cytokines; experimental autoimmune encephalomyelitis