Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation
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van Horssen et al. Journal of Neuroinflammation 2012, 9:156 http://www.jneuroinflammation.com/content/9/1/156
RESEARCH
Open Access
Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation Jack van Horssen1*†, Shailender Singh2,3†, Susanne van der Pol1, Markus Kipp3,4, Jamie L Lim1, Laura Peferoen2, Wouter Gerritsen2, Evert-Jan Kooi2, Maarten E Witte2, Jeroen JG Geurts5, Helga E de Vries1, Regina Peferoen-Baert2, Peter J van den Elsen2,6, Paul van der Valk2 and Sandra Amor2,7
Abstract Background: In brain tissues from multiple sclerosis (MS) patients, clusters of activated HLA-DR-expressing microglia, also referred to as preactive lesions, are located throughout the normal-appearing white matter. The aim of this study was to gain more insight into the frequency, distribution and cellular architecture of preactive lesions using a large cohort of well-characterized MS brain samples. Methods: Here, we document the frequency of preactive lesions and their association with distinct white matter lesions in a cohort of 21 MS patients. Immunohistochemistry was used to gain further insight into the cellular and molecular composition of preactive lesions. Results: Preactive lesions were observed in a majority of MS patients (67%) irrespective of disease duration, gender or subtype of disease. Microglial clusters were predominantly observed in the vicinity of active demyelinating lesions and are not associated with T cell infiltrates, axonal alterations, activated astrocytes or blood–brain barrier disruption. Microglia in preactive lesions consistently express interleukin-10 and TNF-α, but not interleukin-4, whereas matrix metalloproteases-2 and −9 are virtually absent in microglial nodules. Interestingly, key subunits of the free-radical-generating enzyme NADPH oxidase-2 were abundantly expressed in microglial clusters. Conclusions: The high frequency of preactive lesions suggests that it is unlikely that most of them will progress into full-blown demyelinating lesions. Preactive lesions are not associated with blood–brain barrier disruption, suggesting that an intrinsic trigger of innate immune activation, rather than extrinsic factors crossing a damaged blood–brain barrier, induces the formation of clusters of activated microglia. Keywords: Multiple sclerosis, Microglial cells, Preactive lesion, Immune activation, Lesion development
Background Multiple sclerosis (MS) is a chronic, progressive, inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Examination of brain tissue of individuals with MS reveals focal lesions throughout the white matter and extensive demyelination in the cerebral cortex of chronic MS patients [1]. * Correspondence: [email protected] † Equal contributors 1 Department of Molecular Cell Biology and Immunology/Neuropathology, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands Full list of author information is available at the end of the article
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