Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions

Abstract

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease. In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter. In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions. In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage. Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique. Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions. Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression.

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Excessive iron can trigger microglial release of proinflammatory cytokines (such as TNF-α, IL-6, and IL-1β) and/or accentuate production of ROS that disturbs the function of adjacent cell types (101,104,114,116). Microglia are iron loaded in active lesions of multiple sclerosis (118), and activated microglia are associated with increased iron uptake and retention in models of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease (107,109,114,(118)(119)(120). It is clear that microglia play a critical role in the maintenance of brain iron homeostasis; however, more work is needed to elucidate the mechanisms and conditions in which microglial iron cycling contributes to and/or is protective against neural disorder.…”

Myeloid Cells in Multiple Sclerosis

“…Interestingly TMEM119+ cells that express low or no P2RY12 (likely activated microglia) are found within chronically active or slow-expanding lesions, and their density decreases inward. Strikingly, there are no differences between overall M/M density and levels of activation between lesion types [97,100,103].…”

“…Microglia/macrophages (M/Ms) in active MS lesions are heterogeneous and capable of performing a variety of activities that may promote or control inflammation and repair [98,99]. M/Ms found within active MS lesions usually express markers associated with inflammatory macrophage functions, including inducible nitric oxide synthase (iNOS), co-stimulatory molecules CD40 and CD86, the Fc receptors CD32 and CD64, phagocytosis marker CD68, and p22phox, a subunit of NADPH oxidase [100,101]. In addition, M/Ms may also express anti-inflammatory markers such as the mannose receptor CD206 and the scavenger receptor CD163 [100].…”

“…M/Ms found within active MS lesions usually express markers associated with inflammatory macrophage functions, including inducible nitric oxide synthase (iNOS), co-stimulatory molecules CD40 and CD86, the Fc receptors CD32 and CD64, phagocytosis marker CD68, and p22phox, a subunit of NADPH oxidase [100,101]. In addition, M/Ms may also express anti-inflammatory markers such as the mannose receptor CD206 and the scavenger receptor CD163 [100]. Approximately half of the myeloid cells within active lesions express TMEM119, suggesting these cells may be microglia.…”

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

“…Regarding the use of MRI for microgliosis identification, less studies have tried to directly characterize microglial activation in specific brain regions. Changes of iron deposition, quantified using quantitative susceptibility mapping in MR, have been correlated with activated microglia/macrophages at edges of some chronic demyelinated lesions in patients suffering from multiple sclerosis (Dal-Bianco et al, 2017;Gillen et al, 2018;Hametner et al, 2018). Advanced diffusion models, based on neurite orientation dispersion and density imaging (NODDI) in MR, have been proved to be sensitive to microglial density and to the cellular changes associated with microglial activation in a preclinical setting (Yi et al, 2019).…”