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Cardiotrophin-Like Cytokine Increases Macrophage–Foam Cell Transition

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Cardiotrophin-Like Cytokine Increases Macrophage–Foam Cell Transition Cardiotrophin-like Cytokine Increases Macrophage−Foam Cell Transition Sarah Pasquin, Véronique Laplante, Shiriane Kouadri, Andreea Milasan, Gaétan Mayer, Aurélie Jeanne Tormo, This information is current as Virginia Savin, Mukut Sharma, Catherine Martel and of October 7, 2021. Jean-François Gauchat J Immunol published online 12 September 2018 http://www.jimmunol.org/content/early/2018/09/11/jimmun ol.1800733 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 7, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 12, 2018, doi:10.4049/jimmunol.1800733 The Journal of Immunology Cardiotrophin-like Cytokine Increases Macrophage–Foam Cell Transition Sarah Pasquin,* Ve´ronique Laplante,* Shiriane Kouadri,* Andreea Milasan,† Gae´tan Mayer,‡ Aure´lie Jeanne Tormo,x Virginia Savin,{ Mukut Sharma,{ Catherine Martel,† and Jean-Franc¸ois Gauchat* CLCF1 is a neurotrophic and B cell–stimulating factor belonging to the IL-6 family. Mutations in the gene coding for CLCF1 or its secretion partner CRLF1 lead to the development of severe phenotypes, suggesting important nonredundant roles in devel- opment, metabolism, and immunity. Although CLCF1 was shown to promote the proliferation of the myeloid cell line M1, its roles on myeloid activation remain underinvestigated. We characterized the effects of CLCF1 on myeloid cells with a focus on monocyte–macrophage and macrophage–foam cell differentiations. CLCF1 injections in mice resulted in a significant increase + in CD11b circulating cells, including proinflammatory monocytes. Furthermore, CLCF1 activated STAT3 phosphorylation in Downloaded from bone marrow CD11b+ cells and in bone marrow–derived macrophages (BMDM). BMDM stimulated with CLCF1 produced a large array of proinflammatory factors comprising IL-6, IL-9, G-CSF, GM-CSF, IL-1b, IL-12, CCL5, and CX3CL1. The pattern of cytokines and chemokines released by CLCF1-treated BMDM led us to investigate the role of CLCF1 in foam cell formation. When pretreated with CLCF1, BMDM presented a marked SR-A1 upregulation, an increase in acetylated–low-density lipopro- tein uptake, and an elevated triglyceride accumulation. CLCF1-induced SR-A1 upregulation, triglyceride accumulation, and acetylated–low-density lipoprotein uptake could be prevented using ruxolitinib, a JAK inhibitor, indicating that the effects of http://www.jimmunol.org/ the cytokine on myeloid cells result from activation of the canonical JAK/STAT signaling pathway. Our data reveal novel biological roles for CLCF1 in the control of myeloid function and identify this cytokine as a strong inducer of macrophage–foam cell transition, thus bringing forward a new potential therapeutic target for atherosclerosis. The Journal of Immunology, 2018, 201: 000–000. therosclerosis is an inflammatory, lipid-driven pathology vascular smooth muscle cells from the media to the fatty lesions, characterized by the development of atherosclerotic contributing to plaque destabilization and vessel disruption (6, 7). plaques in the artery wall (1). When destabilized, these A better understanding of the biological mechanisms underlying A by guest on October 7, 2021 plaques can lead to vessel disruption, causing blood clots and macrophage–foam cell differentiation could lead to the develop- myocardial infarction (2). Atherosclerotic plaques are the result of ment of effective therapies for the treatment of atherosclerosis. lipid-rich cellular accumulation by macrophages, leading to the The gene coding for sortilin, SORT1, has been implicated in formation of foam cells (3–5). Foam cells have a decreased ability low-density lipoprotein (LDL)/cholesterol metabolism, very LDL to migrate and are inefficient at clearing dead cells, causing ne- (VLDL) secretion, and development of atherosclerotic lesions crotic cores in the vessels. Furthermore, foam cells secrete cyto- (8, 9). Sortilin, a ligand for apolipoprotein E (ApoE), LDL, and kines that induce the activation of T cells surrounding the VLDL (10, 11), was recently shown to interact with the composite atherosclerotic lesions. Activated T cells trigger the migration of CLCF1/CRLF1 (12, 13). CLCF1 is an IL-6 family cytokine shown to activate the ciliary neurotrophic factor receptor (CNTFR) (14– 17). Mutations in the gene coding for CLCF1 or its secretion *De´partement de Pharmacologie et Physiologie, Universite´ de Montre´al, Montreal, partner CRLF1 are associated with cold-induced sweating or Quebec H3T 1J4, Canada; †De´partement de Me´decine, Universite´ de Montre´al, Montreal, Quebec H3T 1J4, Canada; ‡Faculte´ de Pharmacie, Universite´ de Montre´al, Crisponi syndrome, which have overlapping phenotypes (18–21). Montreal, Quebec H3T 1J4, Canada; xImmuniT, Montreal, Quebec H2X 1Y4, Canada; Besides dimorphisms, patients tend to suffer from sterile fever { and Renal Division, Kansas City Veterans Affairs Medical Center, Kansas City, episodes in infancy, recurrent infections, life-threatening feeding MO 64128-2226 difficulties, and disinterest in food, suggesting a role for the cy- ORCIDs: 0000-0002-6433-3627 (A.M.); 0000-0003-1328-2169 (A.J.T.). tokine in the regulation of inflammation and metabolism (21). In Received for publication May 24, 2018. Accepted for publication August 16, 2018. mice, transgenic overexpression of CLCF1 led to splenomegaly This work was supported by Canadian Institutes of Health Research Grant MOP- and hypergammaglobulinemia (15). Hemizygous CLCF1 mice 57832 (to J.-F.G.). C.M. is the recipient of a Fonds de Recherche Sante´ Que´bec Research Scholars Career Award Junior 1. present significantly lower circulating leukocytes (http://www. 2/2 Address correspondence and reprint requests to Dr. Jean-Franc¸ois Gauchat, De´parte- mousephenotype.org/), whereas CRLF1 mice (defective for ment de Pharmacologie et Physiologie, Universite´ de Montre´al, Pavillon Roger Gau- CLCF1 secretion) display a strong reduction in bone marrow dry S455, 2900 Edouard Montpetit, Montreal, QC H3T 1J4, Canada. E-mail address: (BM) hematopoietic stem cells (22). Taken together, these obser- [email protected] vations strongly suggest underexplored immunoregulatory roles for Abbreviations used in this article: ac-LDL, acetylated-LDL; ApoE, apolipoprotein E; BM, bone marrow; BMDM, BM-derived macrophage; CNTFR, ciliary neurotrophic CLCF1. factor receptor; CT-1, cardiotrophin-1; iNOS, inducible NO synthase; LDL, low- Recently, we observed that CLCF1 can interact with ApoE, LDL, density lipoprotein; MHC II, MHC class II; SR-A1, scavenger receptor A 1; VLDL, and VLDL and that CLCF1 binding to VLDL modulates the ac- very LDL. tivation of CNTFR, suggesting that CLCF1 is involved in the Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 dysregulation of lipid metabolism (23). This led us to investigate www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800733 2 CLCF1 PROMOTES FOAM CELL FORMATION the capability of CLCF1 to activate myeloid cells and induce foam CXNFT; Thermo Fisher Scientific), and 1 mg/test anti–IL-12/IL-23 p40-PE cell differentiation. Results indicate that CLCF1 promotes mac- (clone: C17.8; Thermo Fisher Scientific) in permeabilization buffer for rophage activation, scavenger receptor A 1 (SR-A1) expression, 30 min at room temperature. LDL influx, and foam cell formation. These observations suggest Arginase-1 quantification assay a novel role of CLCF1 in the pathogenesis of atherosclerosis. BMDM were stimulated for 18 h with CLCF1, IFN-g/LPS, or IL-4/IL-13 as described above. Cells were harvested, washed, and lysed for 10 min in Materials and Methods 10 mM Tris-HCL (pH 7.4) containing 1 mM pepstatin A, 1 mM leupeptin, CLCF1 injections in mice and 0.4% (w/v) Triton X-100. Arginase activity was then measured using the Arginase Activity Assay Kit (MAK112; Sigma-Aldrich). Production, purification, and testing of recombinant murine CLCF1 and biotinylated CLCF1 was done as described previously (23). All procedures Cytokines and chemokines quantification conformed to the Canadian Council on Animal Care guidelines and were BMDM were stimulated for 18 h with CLCF1, IFN-g/LPS, or IL-4/IL-13 as approved by the Animal Ethics Committee of the Universite´ de Montre´al. described above. Cell supernatants were collected and analyzed using Eve Six-week-old female C57BL/6 mice were purchased from Charles River Technologies 44-Plex Mouse Cytokines/Chemokines Array (Eve Tech- Laboratories (Saint-Constant, QC). i.p. injections of vehicle (PBS nologies, Calgary, AB). IL-6 production by BMDM was confirmed using 0.1% BSA) or CLCF1 (50 or 300 mg/kg) were administered daily for 5 d, quantitative ELISA according to manufacturer’s instructions (Thermo and mice were euthanized by CO inhalation on day 8. WBC were ana- 2 Fisher Scientific). lyzed
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