Abstract
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) characterized by the presence of focal demyelinated plaques. Sufficient clearance of myelin and cellular debris is one of the requirements for proper tissue repair and remyelination. The mechanisms underlying the clearance of such debris by phagocytes are not fully understood, but recent findings suggest a prominent role for lipoprotein-lipase (LPL) in this process. Here, we demonstrate that angiopoietin-like 4 (ANGPTL4), a potent inhibitor of LPL, is abundantly expressed in astrocytes in control white matter tissue and its expression is markedly reduced in active MS lesions. We provide evidence that ANGPTL4 inhibits the uptake of myelin-derived lipids by LPL-immunoreactive phagocytes. Taken together, our data suggest that the strong reduction in astrocytic ANGPTL4 expression in active demyelinating MS lesions enables phagocytes to adequately clear myelin debris, setting the stage for remyelination.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease characterized by massive infiltration of monocytederived macrophages into the central nervous system (CNS)
We previously demonstrated that angiopoietin-like 4 (ANGPTL4) is expressed by astrocytes in white matter and in gray matter of patients suffering from capillary cerebral amyloid angiopathy [8]
We show that the astrocytic expression of ANGPTL4 is markedly reduced in active demyelinating MS lesions compared to surrounding normal appearing white matter (NAWM)
Summary
MS is an inflammatory demyelinating disease characterized by massive infiltration of monocytederived macrophages into the central nervous system (CNS). Intravenous administration of anti-inflammatory macrophages or microglia reduced clinical signs in the MS animal model experimental autoimmune encephalomyelitis (EAE) [2, 3]. The cellular mechanisms involved in clearance of myelin debris by phagocytes are poorly understood, evidence is emerging that lipoprotein-lipase (LPL), an enzyme involved in lipid-processing, plays an important role during initiation of remyelination [4, 6]. Activity of this enzyme is significantly increased in brain tissue of the EAE model at the point
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