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Is Open Access

Monocyte Chemoattractant Protein-1 (MCP-1) Regulates Macrophage Cytotoxicity in Abdominal Aortic Aneurysm

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      In abdominal aortic aneurysm (AAA), macrophages are detected in the proximity of aortic smooth muscle cells (SMCs). We have previously demonstrated in a murine model of AAA that apoptotic SMCs attract monocytes and other leukocytes by producing MCP-1. Here we tested whether infiltrating macrophages also directly contribute to SMC apoptosis.

      Methods and Results

      Using a SMC/RAW264.7 macrophage co-culture system, we demonstrated that MCP-1-primed RAWs caused a significantly higher level of apoptosis in SMCs as compared to control macrophages. Next, we detected an enhanced Fas ligand (FasL) mRNA level and membrane FasL protein expression in MCP-1-primed RAWs. Neutralizing FasL blocked SMC apoptosis in the co-culture. In situ proximity ligation assay showed that SMCs exposed to primed macrophages contained higher levels of receptor interacting protein-1 (RIP1)/Caspase 8 containing cell death complexes. Silencing RIP1 conferred apoptosis resistance to SMCs. In the mouse elastase injury model of aneurysm, aneurysm induction increased the level of RIP1/Caspase 8 containing complexes in medial SMCs. Moreover, TUNEL-positive SMCs in aneurysmal tissues were frequently surrounded by CD68 +/FasL + macrophages. Conversely, elastase-treated arteries from MCP-1 knockout mice display a reduction of both macrophage infiltration and FasL expression, which was accompanied by diminished apoptosis of SMCs.


      Our data suggest that MCP-1-primed macrophages are more cytotoxic. MCP-1 appears to modulate macrophage cytotoxicity by increasing the level of membrane bound FasL. Thus, we showed that MCP-1-primed macrophages kill SMCs through a FasL/Fas-Caspase8-RIP1 mediated mechanism.

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      Most cited references 44

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      Direct observation of individual endogenous protein complexes in situ by proximity ligation.

      Cellular processes can only be understood as the dynamic interplay of molecules. There is a need for techniques to monitor interactions of endogenous proteins directly in individual cells and tissues to reveal the cellular and molecular architecture and its responses to perturbations. Here we report our adaptation of the recently developed proximity ligation method to examine the subcellular localization of protein-protein interactions at single-molecule resolution. Proximity probes-oligonucleotides attached to antibodies against the two target proteins-guided the formation of circular DNA strands when bound in close proximity. The DNA circles in turn served as templates for localized rolling-circle amplification (RCA), allowing individual interacting pairs of protein molecules to be visualized and counted in human cell lines and clinical specimens. We used this method to show specific regulation of protein-protein interactions between endogenous Myc and Max oncogenic transcription factors in response to interferon-gamma (IFN-gamma) signaling and low-molecular-weight inhibitors.
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        Transcriptional regulation of macrophage polarization: enabling diversity with identity.

        In terms of both phenotype and function, macrophages have remarkable heterogeneity, which reflects the specialization of tissue-resident macrophages in microenvironments as different as liver, brain and bone. Also, marked changes in the activity and gene expression programmes of macrophages can occur when they come into contact with invading microorganisms or injured tissues. Therefore, the macrophage lineage includes a remarkable diversity of cells with different functions and functional states that are specified by a complex interplay between microenvironmental signals and a hardwired differentiation programme that determines macrophage identity. In this Review, we summarize the current knowledge of transcriptional and chromatin-mediated control of macrophage polarization in physiology and disease.
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          TNF-alpha induces two distinct caspase-8 activation pathways.

          The inflammatory response of mammalian cells to TNF-alpha can be switched to apoptosis either by cotreatment with a protein synthesis inhibitor, cycloheximide, or Smac mimetic, a small molecule mimic of Smac/Diablo protein. Cycloheximide promotes caspase-8 activation by eliminating endogenous caspase-8 inhibitor, c-FLIP, while Smac mimetic does so by triggering autodegradation of cIAP1 and cIAP2 (cIAP1/2), leading to the release of receptor interacting protein kinase (RIPK1) from the activated TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8. This process also requires the action of CYLD, a RIPK1 K63 deubiquitinating enzyme. RIPK1 is critical for caspase-8 activation-induced by Smac mimetic but dispensable for that triggered by cycloheximide. Moreover, Smac mimetic-induced caspase-8 activation is not blocked by endogenous c-FLIP. These findings revealed that TNF-alpha is able to induce apoptosis via two distinct caspase-8 activation pathways that are differentially regulated by cIAP1/2 and c-FLIP.

            Author and article information

            [1 ]Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, United States of America
            [2 ]Luye Pharma Group, Yantai, China
            Albert Einstein College of Medicine, United States of America
            Author notes

            Competing Interests: CD was an employee of Luye Pharma at the time of the study. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

            Conceived and designed the experiments: BL QW. Performed the experiments: QW JR SM ZL. Analyzed the data: QW JR CD. Wrote the paper: QW BL CD.


            Current address: Binzhou Medical University, Yantai High-tech Zone, China

            Role: Editor
            PLoS One
            PLoS ONE
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            14 March 2014
            : 9
            : 3
            24632850 3954911 PONE-D-13-43085 10.1371/journal.pone.0092053

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Pages: 10
            This work was supported by the National Institute of Health R01HL088447 (BL) and the Ruth L. Kirschstein National Research Service Award T32 HL 07936 and T32 HL110853 from the National Heart Lung and Blood Institute to the University of Wisconsin-Madison Cardiovascular Research Center and Department of Surgery (SM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Research Article
            Biology and Life Sciences
            Cardiovascular Anatomy
            Cell Biology
            Cell Processes
            Cell Death
            Signal Transduction
            Cell Signaling
            Signaling Cascades
            Apoptotic Signaling Cascade
            Apoptotic Signaling
            Molecular Cell Biology
            Developmental Biology
            Molecular Development
            Immune Response
            Immune System
            Immune Physiology
            Medicine and Health Sciences
            Vascular Medicine
            Vascular Diseases
            Peripheral Vascular Disease



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