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Transcription factor NF-kappaB and inhibitor I kappaBalpha are localized in macrophages in active multiple sclerosis
D Gveric1, C Kaltschmidt, M L Cuzner
1Multiple Sclerosis Laboratory, Institute of Neurology, London, England.
Abstract:
NF-kappaB is a transcription factor family which on translocation to the nucleus regulates gene expression during cell activation. As such, NF-kappaB may play a role in the microglial response to myelin damage in multiple sclerosis (MS) lesions. Here the cellular localization of NF-kappaB and expression of the inhibitory I kappaBalpha were examined by immunocytochemistry on central nervous system (CNS) tissue from MS and control cases. In normal control white matter, the active form of the NF-kappaB subunit RelA (p65) was localized in microglial nuclei, while the c-Rel and p50 subunits and the inhibitory I kappaBalpha were restricted to the cytoplasm. In contrast, in actively demyelinating plaques, the RelA, c-Rel, and p50 subunits of NF-kappaB and I kappaBalpha were all present in macrophage nuclei in both parenchymal and perivascular areas. RelA was also found in the nuclei of a subset of hypertrophic astrocytes. Only c-Rel had a nuclear localization in lymphocytes in perivascular inflammatory cuffs. Our results suggest that constitutive activation of the RelA subunit in the nuclei of resting microglia may facilitate a rapid response to pathological stimuli in the CNS. Activation of the inducible NF-kappaB pool in macrophages in MS lesions could amplify the inflammatory reaction through upregulation of NF-kappaB-controlled adhesion molecules and cytokines.
Insights
Nuclear factor-kappa B (NF-kappaB) activation in microglia and macrophages is implicated in multiple sclerosis (MS) pathology. This study reveals NF-kappaB subunit localization in CNS tissue from MS patients, suggesting a role in inflammatory responses.
Area of Science:
- Neuroimmunology
- Molecular Biology
Background:
- Nuclear factor-kappa B (NF-kappaB) is a crucial transcription factor family regulating gene expression during cellular activation.
- NF-kappaB may play a significant role in the microglial response to myelin damage observed in multiple sclerosis (MS) lesions.
Purpose of the Study:
- To investigate the cellular localization of NF-kappaB subunits and the expression of its inhibitor, I kappaBalpha, in the central nervous system (CNS) of MS patients and controls.
Main Methods:
- Immunocytochemistry was employed to examine CNS tissue samples from both MS and control cases.
- The study focused on the distribution of specific NF-kappaB subunits (RelA, c-Rel, p50) and I kappaBalpha.
Main Results:
- In normal white matter, active NF-kappaB (RelA) was nuclear in microglia, while other components were cytoplasmic.
- In active MS plaques, NF-kappaB subunits and I kappaBalpha were found in the nuclei of macrophages and, in some cases, astrocytes and lymphocytes.
- Constitutive nuclear RelA was observed in resting microglia, suggesting a rapid response mechanism.
Conclusions:
- Constitutive activation of the RelA subunit in microglia may prime the CNS for rapid responses to pathological stimuli.
- Inducible NF-kappaB activation in macrophages within MS lesions could exacerbate inflammation by upregulating adhesion molecules and cytokines.