| First Author | Avloniti M | Year | 2024 |
| Journal | J Neuroinflammation | Volume | 21 |
| Issue | 1 | Pages | 34 |
| PubMed ID | 38279130 | Mgi Jnum | J:352931 |
| Mgi Id | MGI:7580008 | Doi | 10.1186/s12974-024-03023-9 |
| Citation | Avloniti M, et al. (2024) IKKbeta deletion from CNS macrophages increases neuronal excitability and accelerates the onset of EAE, while from peripheral macrophages reduces disease severity. J Neuroinflammation 21(1):34 |
| abstractText | BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease characterized by motor deficits and cognitive decline. Many immune aspects of the disease are understood through studies in the experimental autoimmune encephalomyelitis (EAE) model, including the contribution of the NF-kappaB transcription factor to neuroinflammation. However, the cell-specific roles of NF-kappaB to EAE and its cognitive comorbidities still needs further investigation. We have previously shown that the myeloid cell NF-kappaB plays a role in the healthy brain by exerting homeostatic regulation of neuronal excitability and synaptic plasticity and here we investigated its role in EAE. METHODS: We used constitutive MphiIKKbetaKappaOmicron mice, in which depletion of IKKbeta, the main activating kinase of NF-kappaB, was global to CNS and peripheral macrophages, and MugIotaKappaKappabetaKO mice, in which depletion was inducible and specific to CNS macrophages by 28 days after tamoxifen administration. We subjected these mice to MOG(35-55) induced EAE and cuprizone-induced demyelination. We measured pathology by immunohistochemistry, investigated molecular mechanisms by RNA sequencing analysis and studied neuronal functions by in vivo electrophysiology in awake animals. RESULTS: Global depletion of IKKbeta from myeloid cells in MphiIKKbetaKappaOmicron mice accelerated the onset and significantly supressed chronic EAE. Knocking out IKKbeta only from CNS resident macrophages accelerated the onset and exacerbated chronic EAE, accompanied by earlier demyelination and immune cell infiltration but had no effect in cuprizone-induced demyelination. Peripheral T cell effector functions were not affected by myeloid cell deletion of IKKbeta, but CNS resident mechanisms, such as microglial activation and neuronal hyperexcitability were altered from early in EAE. Lastly, depletion of myeloid cell IKKbeta resulted in enhanced late long-term potentiation in EAE. CONCLUSIONS: IKKbeta-mediated activation of NF-kappaBeta in myeloid cells has opposing roles in EAE depending on the cell type and the disease stage. In CNS macrophages it is protective while in peripheral macrophages it is disease-promoting and acts mainly during chronic disease. Although clinically protective, CNS myeloid cell IKKbeta deletion dysregulates neuronal excitability and synaptic plasticity in EAE. These effects of IKKbeta on brain cognitive abilities deserve special consideration when therapeutic interventions that inhibit NF-kappaB are used in MS. |
