Journal Article

Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation

Kooi, Evert-Jan, Geurts, Jeroen JG, Amor, Sandra, van der Pol, Susanne, Lim, Jamie L, Peferoen-Baert, Regina, Singh, Shailender, Kipp, Markus, Gerritsen, Wouter, van den Elsen, Peter J, van Horssen, Jack, Peferoen, Laura, Witte, Maarten E, de Vries, Helga E, van der Valk, Paul

2012

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Aged / Aged, 80 and over / Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Brain / Brain - immunology / Brain - metabolism / Brain - pathology / Brain damage / Cohort Studies / Development and progression / Drinking water / Humans / Immune activation / Immunity, Innate / Immunohistochemistry / Immunology / Interleukins / Lesion development / Microglia - cytology / Microglia - immunology / Microglia - metabolism / Microglial cells / Middle Aged / Multiple sclerosis / Multiple Sclerosis - immunology / Multiple Sclerosis - metabolism / Multiple Sclerosis - pathology / Natural immunity / Nerve Fibers, Myelinated - immunology / Nerve Fibers, Myelinated - metabolism / Neurobiology / Neurology / Neurosciences / Nitric oxide / Oxidases / Physiological aspects / Preactive lesion / Proteases / Proteins / T cells