Abstract
Most multiple sclerosis (MS) patients develop over time a secondary progressive disease course, characterized histologically by axonal loss and atrophy. In early phases of the disease, focal inflammatory demyelination leads to functional impairment, but the mechanism of chronic progression in MS is still under debate. Reactive oxygen species generated by invading and resident central nervous system (CNS) macrophages have been implicated in mediating demyelination and axonal damage, but demyelination and neurodegeneration proceed even in the absence of obvious immune cell infiltration, during clinical recovery in chronic MS. Here, we employ intravital NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX1–4, DUOX1, 2) and, thus, to identify the cellular source of oxidative stress in the CNS of mice affected by experimental autoimmune encephalomyelitis (EAE) in the remission phase of the disease. This directly affects neuronal function in vivo, as monitored by cellular calcium levels using intravital FRET–FLIM, providing a possible mechanism of disease progression in MS.
Highlights
Multiple sclerosis (MS) is a chronic neuroinflammatory disease, with most patients exhibiting a relapsing and remitting course of disease
Reactive oxygen species (ROS) generated by invading and resident central nervous system (CNS) macrophages have been implicated in mediating demyelination and axonal damage (6–8)
Our aim was to first characterize peripheral and CNS resident cellular compartments during the remission phase by means of intravital imaging and to corroborate previous results concerning the lack of overt inflammation in this phase
Summary
Multiple sclerosis (MS) is a chronic neuroinflammatory disease, with most patients exhibiting a relapsing and remitting course of disease. Macrophages/ microglia, B, and T cells create an acute inflammatory setting, resulting in demyelination and neuronal damage. “Old” lesions appear morphologically inert and are characterized by single perivascular T cells, minimal axonal damage in histological stainings with anti-amyloid precursor protein (APP) antibodies and a dominant fibrotic glial scar (4, 5). In contrast to the progressive disease phase, the inflammatory phase is well modeled by murine experimental autoimmune encephalomyelitis (EAE). In this mouse model using an immunization with MOG35–55 peptide, acute clinical signs remit after a few days and mice enter into a chronic phase with or without a residuum of neurological deficits (1).
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