SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL

Choi, Soo–Ho; Gonen, Ayelet; Diehl, Cody J.; Kim, Jung-Su; Almazan, Felicidad; Witztum, Joseph L.; Miller, Yury I.

doi:10.1080/15548627.2015.1037061

Cited by 62 publications

(44 citation statements)

References 47 publications

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“…However, the mechanism of ox-LDL in autophagy regulation remains controversial. Some studies indicate that ox-LDL induces autophagosome and autolysosome formation by upregulating expression of OLR1 47,48 or peroxisome proliferator-activated receptor gamma (PPARG) 49 and their downstream production of reactive oxygen species (ROS). Excessive generated ROS in response to damaged mitochondria which escape from autophagy, causes cellular dysfunction and cell death.…”

Section: Discussionmentioning

confidence: 99%

Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure

Yang

et al. 2016

Autophagy

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Improving biological functions of endothelial progenitor cells (EPCs) is beneficial to maintaining endothelium homeostasis and promoting vascular re-endothelialization. Because macroautophagy/ autophagy has been documented as a double-edged sword in cell functions, its effects on EPCs remain to be elucidated. This study was designed to explore the role and molecular mechanisms of store-operated calcium entry (SOCE)-activated autophagy in proliferation of EPCs under hypercholesterolemia. We employed oxidized low-density lipoprotein (ox-LDL) to mimic hypercholesterolemia in bone marrowderived EPCs from rat. Ox-LDL dose-dependently activated autophagy flux, while inhibiting EPC proliferation. Importantly, inhibition of autophagy either by silencing Atg7 or by 3-methyladenine treatment, further aggravated proliferative inhibition by ox-LDL, suggesting the protective effects of autophagy against ox-LDL. Interestingly, ox-LDL increased STIM1 expression and intracellular Ca 2C concentration. Either Ca 2C chelators or deficiency in STIM1 attenuated ox-LDL-induced autophagy activation, confirming the involvement of SOCE in the process. Furthermore, CAMKK2 (calcium/ calmodulin-dependent protein kinase kinase 2, b) activation and MTOR (mechanistic target of rapamycin [serine/threonine kinase]) deactivation were associated with autophagy modulation. Together, our results reveal a novel signaling pathway of SOCE-CAMKK2 in the regulation of autophagy and offer new insights into the important roles of autophagy in maintaining proliferation and promoting the survival capability of EPCs. This may be beneficial to improving EPC transplantation efficacy and enhancing vascular reendothelialization in patients with hypercholesterolemia.

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Section: Discussionmentioning

confidence: 99%

Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure

Yang

et al. 2016

Autophagy

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“…CyPA can be secreted from RASMC in response to the ROS inducer LY83583 [11,12]. ox-LDL, as a proatherogenic factor, induces intracellular production of ROS in various cell types such as VSMC [8,9,10] and macrophages [26,27,28]. It has been reported that ox-LDL induces CyPA secretion from THP-1 via an unknown mechanism [29].…”

Section: Discussionmentioning

confidence: 99%

Oxidized Low-Density Lipoprotein-Induced Cyclophilin A Secretion Requires ROCK-Dependent Diphosphorylation of Myosin Light Chain

Lin²,

Chen³

et al. 2016

J Vasc Res

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Objective: Accumulation of cyclophilin A (CyPA) within atherosclerotic lesions is thought to be implicated in the progression of atherosclerosis. However, the source of CyPA within atherosclerotic lesions is still unknown. The aim of this study is to determine the role of oxidized low-density lipoproteins (ox-LDL) in vascular smooth muscle cell (VSMC)-derived CyPA secretion and the underlying mechanism. Methods and Results: Abundant CyPA and α-smooth muscle actin (α-SMA) expressed in atherosclerotic lesions was observed in apolipoprotein E-deficient mice. ox-LDL induced CyPA secretion from a primary culture of rat aortic smooth muscle cells in a dose- and time-dependent manner. Sulfosuccinimidyloleate, a CD36 inhibitor, prevented the ox-LDL-induced CyPA secretion. Pre-exposure to either the actin-depolymerizing agent cytochalasin D or the actin-polymerizing agent jasplakinolide inhibited CyPA secretion induced by ox-LDL. Gene silencing of vesicle-associated membrane protein 2 suppressed ox-LDL-induced CyPA secretion. ox-LDL caused the phosphorylation of myosin light chain (MLC). Inhibition of MLC by blebbistatin reversed the secretion of CyPA and the phosphorylation of MLC induced by ox-LDL. MLC kinase inhibitor ML-7 reduced the monophosphorylation of MLC but did not reduce CyPA secretion. Pretreatment with the rho-associated coiled-coil kinase (ROCK) inhibitor Y27632 blocked diphosphorylation of MLC and secretion of CyPA induced by ox-LDL. Conclusions: ox-LDL-induced CyPA secretion requires vesicle transportation, actin remodeling and ROCK-dependent diphosphorylation of MLC. VSMC-derived CyPA induced by ox-LDL may be associated with increased CyPA expression in atherosclerotic lesions.

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“…Furthermore, Abcg1 −/− macrophages have been shown to display enhanced proinflammatory cytokine production (117, 118). OxLDL induces autophagosome formation, MHC-II expression, and phosphorylation of SYK in macrophages (119). Several studies have suggested a role for cholesterol in the development and maturation of dendritic cells.…”

Section: Effects Of Cholesterol On Antigen Presenting Cellsmentioning

confidence: 99%

Impact of hyperlipidemia on alloimmunity

Bagley

Yuan

Iacomini

2017

Current Opinion in Organ Transplantation

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Purpose of Review Hyperlipidemia is a co-morbidity affecting a significant number of transplant patients despite treatment with cholesterol lowering drugs. Recently it has been shown that hyperlipidemia can significantly alter T cell responses to cardiac allografts in mice, and graft rejection is accelerated in dyslipidemic mice. Here we review recent advances in our understanding of hyperlipidemia in graft rejection. Recent Findings Hyperlipidemic mice have significant increases in serum levels of pro-inflammatory cytokines, and neutralization of IL-17 slows graft rejection, suggesting that IL-17 production by Th17 cells was necessary but not sufficient for rejection. Hyperlipidemia also causes an increase in alloreactive T cell responses prior to antigen exposure. Analysis of peripheral tolerance mechanisms indicated that this was at least in part due to alterations in FoxP3+ T cells that led to reduced Treg function and the expansion of FoxP3+ CD4 T cells expressing low levels of CD25. Functionally, alterations in Treg function prevented the ability to induce operational tolerance to fully allogeneic heart transplants through costimulatory-molecule blockade, a strategy that requires Tregs. Summary These findings highlight the importance of considering the contribution of inflammatory co-morbidities to cardiac allograft rejection, and point to the potential importance of managing hyperlipidemia in the transplant population.

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SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL

Abstract: I Miller (2015) SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL, Autophagy, 11:5,[785][786][787][788][789][790][791][792][793][794][795]

Cited by 62 publications

References 47 publications

Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure

Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure

Oxidized Low-Density Lipoprotein-Induced Cyclophilin A Secretion Requires ROCK-Dependent Diphosphorylation of Myosin Light Chain

Impact of hyperlipidemia on alloimmunity

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