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Alpha-chlorofatty acid accumulates in activated monocytes and causes apoptosis through reactive oxygen species production and endoplasmic reticulum stress.

ABSTRACT: Myeloperoxidase-enriched monocytes play important roles in inflammatory disease, such as atherosclerosis. We previously demonstrated that ?-chlorofatty aldehydes are produced as a result of plasmalogen targeting by myeloperoxidase-derived hypochlorous acid in activated monocytes. Here, we show ?-chlorofatty acid (?-ClFA), a stable metabolite of ?-chlorofatty aldehydes, accumulates in activated monocytes and mediates the molecular effects of ?-ClFA on monocytes/macrophages.Liquid chromatography-mass spectrometry revealed that ?-ClFA is elevated 5-fold in phorbol myristate-stimulated human monocytes rising to ?20 ?mol/L when compared with unstimulated cells. Using human THP-1 monocytes and RAW 264.7 cells as in vitro models, we tested the hypothesis that ?-ClFA is a cell death mediator that could potentially participate in pathophysiological roles of monocytes in diseases, such as atherosclerosis. Indeed, 2-chlorohexadecanoic acid, the 16-carbon molecular species of ?-ClFA, caused significant apoptosis of primary monocytes. Similarly, 2-chlorohexadecanoic acid also caused apoptosis in THP-1 human monocytes and RAW 264.7 mouse macrophages as determined by annexin V-propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick end labeling staining, respectively. 2-Chlorohexadecanoic acid treatment also increased caspase-3 activity and poly (ADP-ribose) polymerase cleavage in THP-1 cells. 2-Chlorohexadecanoic acid likely elicits apoptosis by increasing both reactive oxygen species production and endoplasmic reticulum stress because antioxidants and CCAAT/enhancer-binding protein homologous protein block such induced cell apoptosis.The stable chlorinated lipid, ?-ClFA, accumulates in activated primary human monocytes and elicits monocyte apoptosis through increased reactive oxygen species production and endoplasmic reticulum stress, providing a new insight into chlorinated lipids and monocytes in inflammatory disease.

SUBMITTER: Wang WY

PROVIDER: S-EPMC3951512 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Alpha-chlorofatty acid accumulates in activated monocytes and causes apoptosis through reactive oxygen species production and endoplasmic reticulum stress.

Wang Wen-yi WY Albert Carolyn J CJ Ford David A DA

Arteriosclerosis, thrombosis, and vascular biology 20131226 3

<h4>Objective</h4>Myeloperoxidase-enriched monocytes play important roles in inflammatory disease, such as atherosclerosis. We previously demonstrated that α-chlorofatty aldehydes are produced as a result of plasmalogen targeting by myeloperoxidase-derived hypochlorous acid in activated monocytes. Here, we show α-chlorofatty acid (α-ClFA), a stable metabolite of α-chlorofatty aldehydes, accumulates in activated monocytes and mediates the molecular effects of α-ClFA on monocytes/macrophages.<h4>A ...[more]

PMID: 24371082

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Project description:PurposeEndoplasmic reticulum (ER) and mitochondrial stress are independently associated with corneal endothelial cell (CEnC) loss in many corneal diseases, including Fuchs' endothelial corneal dystrophy (FECD). However, the role of ER stress in mitochondrial dysfunction contributing to CEnC apoptosis is unknown. The purpose of this study is to explore the crosstalk between ER and mitochondrial stress in CEnC.MethodsHuman corneal endothelial cell line (HCEnC-21T) and human corneal endothelial tissues were treated with ER stressor tunicamycin. ER stress-reducing chemical 4-phenyl butyric acid (4-PBA) was used in HCEnC-21T after tunicamycin. Fuchs' corneal endothelial cell line (F35T) was used to determine differential activation of ER stress with respect to HCEnC-21T at the baseline. ER stress, mitochondrial-mediated intrinsic apoptotic, mitochondrial fission, and fusion proteins were determined using immunoblotting and immunohistochemistry. Mitochondrial bioenergetics were assessed by mitochondrial membrane potential (MMP) loss and ATP production at 48 hours after tunicamycin. Mitochondria dynamics (shape, area, perimeter) were also analyzed at 24 hours using transmission electron microscopy.ResultsTreatment of HCEnC-21T cell line with tunicamycin activated three ER stress pathways (PERK-eIF2α-CHOP, IRE1α-XBP1, and ATF6), reduced cell viability, upregulated mitochondrial-mediated intrinsic apoptotic molecules (cleaved caspase 9, caspase 3, PARP, Bax, cytochrome C), downregulated anti-apoptotic Bcl-2 protein, initiated mitochondrial dysfunction by loss of MMP and lowering of ATP production, and caused mitochondrial swelling and fragmentation with increased expression of mitochondrial fission proteins (Fis1 and p-Drp1). Fuchs' CEnC (F35T) cell line also showed activation of the ER stress-related proteins (p-eIF2α, GRP78, CHOP, XBP1) compared to HCEnC-21T at the baseline. The 4-PBA ameliorated cell loss and reduced cleaved caspase 3 and 9, thereby rescuing tunicamycin-induced cell death but not mitochondrial bioenergetics in HCEnC-21T cell line.ConclusionsTunicamycin-induced ER stress disrupts mitochondrial bioenegetics, dynamics and contributes to the loss of CEnC viability. This novel study highlights the importance of ER-mitochondria crosstalk and its contribution to CEnCs apoptosis, seen in many corneal diseases, including FECD.

Dataset Information

Alpha-chlorofatty acid accumulates in activated monocytes and causes apoptosis through reactive oxygen species production and endoplasmic reticulum stress.

Publications

Alpha-chlorofatty acid accumulates in activated monocytes and causes apoptosis through reactive oxygen species production and endoplasmic reticulum stress.

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