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

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/flmice 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/flmice 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. © 2012 ellrichmann et al; licensee biomed central ltd.