Low‐density lipoprotein receptors regulate microglial inflammation through c‐Jun N‐terminal kinase
- 19 September 2008
- Vol. 57 (4), 444-453
- https://doi.org/10.1002/glia.20772
Abstract
Apolipoprotein E (apoE) has been implicated in modulating the central nervous system (CNS) inflammatory response. However, the molecular mechanisms involved in apoE‐dependent immunomodulation are poorly understood. We hypothesize that apoE alters the CNS inflammatory response by signaling via low‐density lipoprotein (LDL) receptors in glia. To address this hypothesis, we used a small bioactive peptide formed from the receptor‐binding domain of apoE, apoE peptide (EP), to study LDL receptor signaling in microglia. To model glial activation, we treated primary mouse microglia and the microglial cell line BV2 with lipopolysaccharide (LPS) and studied two inflammatory responses: an increase in nitric oxide production (NO) and a decrease in apoE production. We found that treatment of primary microglia and BV2 cells with EP attenuated LPS‐induced NO accumulation and apoE reduction in a dose‐dependent manner. Using the receptor‐associated protein to block ligand binding to members of the LDL receptor family, we found that EP attenuated both of these LPS‐induced inflammatory responses via LDL receptors. We studied two intracellular signaling cascades associated with apoE: c‐Jun N‐terminal kinase (JNK) and extracellular signal‐regulated kinase (ERK). LPS induced both ERK and JNK activation, whereas EP induced ERK activation, but drastically reduced JNK activation. Inhibition of JNK with SP600125 reduced LPS‐induced NO production and apoE reduction in a dose‐dependent manner. Treatment of microglia with suboptimal EP in combination with JNK inhibitor enhanced attenuation of LPS‐induced NO production. These data suggest that microglial LDL receptors regulate JNK activation, which is necessary for apoE modulation of the inflammatory response.This publication has 57 references indexed in Scilit:
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