Wulin Aerbajinai, Jianqiong Zhu, Kyung Chin, Griffin P Rodgers
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引用次数: 0
Abstract
Dysfunctional phagocytic clearance of β-amyloid (Aβ) in microglia and peripheral macrophages/monocytes has been implicated in Alzheimer's disease (AD), but the mechanisms underlying this dysfunction are not yet well understood. In this study, we examined the role of glia maturation factor-γ (GMFG), an actin-disassembly protein that is highly expressed in immune cells, in macrophage Aβ phagocytosis and in regulating scavenger receptor AI (SR-AI), a cell-surface receptor that has previously been implicated in Aβ clearance. GMFG knockdown increased phagocytosis of Aβ42 in BMDMs and RAW264.7 murine macrophages, while GMFG overexpression reduced Aβ42 uptake in these cells. Blocking with anti-SR-AI antibodies inhibited Aβ42 uptake in GMFG-knockdown cells, establishing a role for SR-AI in Aβ42 phagocytosis. GMFG knockdown increased SR-AI protein expression under both basal conditions and in response to Aβ42 treatment via both the transcriptional and post-transcriptional level in RAW264.7 macrophages. GMFG knockdown modulated Aβ42-induced K48-linked and K63-polyubiquitination of SR-AI, the phosphorylation of SR-AI and JNK, suggesting that GMFG plays a role for intracellular signaling in the SR-AI-mediated uptake of Aβ. Further, GMFG-knockdown cells displayed increased levels of the transcriptional factor MafB, and silencing of MafB in these cells reduced their SR-AI expression. Finally, GMFG was found to interact with the nuclear pore complex component RanBP2, and silencing of RanBP2 in GMFG-knockdown cells reduced their SR-AI expression. Collectively, these data support the role of GMFG as a novel regulator of SR-AI in macrophage Aβ phagocytosis, and may provide insight into therapeutic approaches to potentially slow or prevent the progression of AD.
期刊介绍:
JLB is a peer-reviewed, academic journal published by the Society for Leukocyte Biology for its members and the community of immunobiologists. The journal publishes papers devoted to the exploration of the cellular and molecular biology of granulocytes, mononuclear phagocytes, lymphocytes, NK cells, and other cells involved in host physiology and defense/resistance against disease. Since all cells in the body can directly or indirectly contribute to the maintenance of the integrity of the organism and restoration of homeostasis through repair, JLB also considers articles involving epithelial, endothelial, fibroblastic, neural, and other somatic cell types participating in host defense. Studies covering pathophysiology, cell development, differentiation and trafficking; fundamental, translational and clinical immunology, inflammation, extracellular mediators and effector molecules; receptors, signal transduction and genes are considered relevant. Research articles and reviews that provide a novel understanding in any of these fields are given priority as well as technical advances related to leukocyte research methods.