A Role for Neuronal NF-κB in Suppressing Neuroinflammation and Promoting Neuroprotection in the CNS

Nuclear factor-κB (NF-κB) signaling plays a crucial role during inflammatory, demyelinating disease and that becomes evident through opposing proinflammatory and neuroprotective functions that depend on the different cell types in which it is activated. The role of NF-κB activation specifically in neurons during pathological conditions in the central nervous system (CNS) needs to be elucidated. We applied conditional gene targeting in C57Bl6 mice to delete the inhibitor of NF-κB kinase β (IKKβ), a kinase essential for activation of the canonical NF-κB pathway, specifically in CNS neurons and immunized them with MOG35−55 peptide to induce experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. Mice lacking neuronal IKKβ (nIKKβKO) developed a more severe, non-resolving disease compared to control mice with increased axonal damage during the chronic phase. nIKKβKO mice in the early chronic phase of disease showed significantly reduced levels of neuroprotective molecules and enhanced expression of immune mediators that are known to be important for EAE pathogenesis compared to control mice. Additionally, increased proportions of CD4+ and CD4+IFNγ+ cells and decreased proportion of NK1.1+ cells in nIKKβKO mice reveal differences in CNS-infiltrating monocytes between the two groups. Our results show that NF-κB in CNS neurons plays a critical role in modulating the severity of autoimmune demyelinating disease, not only by enhancing neuroprotection but also by suppressing CNS immune responses, and emphasizes the importance of neuroprotective strategies for the treatment of multiple sclerosis.