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Damage and Inflammation Ischemia/Reperfusion-Induced Domain V Peptides Inhibit β2-Glycoprotein I-Mediated Mesenteric Ischemia/Reperfusion-Induced Tissue Damage and Inflammation This information is current as of September 27, 2021. Sherry D. Fleming, Michael R. Pope, Sara M. Hoffman, Tiffany Moses, Urska Bukovnik, John M. Tomich, Lynn M. Wagner and Keith M. Woods J Immunol 2010; 185:6168-6178; Prepublished online 18 October 2010; Downloaded from doi: 10.4049/jimmunol.1002520 http://www.jimmunol.org/content/185/10/6168 http://www.jimmunol.org/ References This article cites 65 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/185/10/6168.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Domain V Peptides Inhibit b2-Glycoprotein I-Mediated Mesenteric Ischemia/Reperfusion-Induced Tissue Damage and Inflammation Sherry D. Fleming,* Michael R. Pope,* Sara M. Hoffman,* Tiffany Moses,† Urska Bukovnik,‡ John M. Tomich,‡ Lynn M. Wagner,* and Keith M. Woods* Reperfusion of ischemic tissue induces significant tissue damage in multiple conditions, including myocardial infarctions, stroke, and transplantation. Although not as common, the mortality rate of mesenteric ischemia/reperfusion (IR) remains >70%. Although complement and naturally occurring Abs are known to mediate significant damage during IR, the target Ags are intracellular molecules. We investigated the role of the serum protein, b2-glycoprotein I as an initiating Ag for Ab recognition and b2- glycoprotein I (b2-GPI) peptides as a therapeutic for mesenteric IR. The time course of b2-GPI binding to the tissue indicated Downloaded from binding and complement activation within 15 min postreperfusion. Treatment of wild-type mice with peptides corresponding to the lipid binding domain V of b2-GPI blocked intestinal injury and inflammation, including cellular influx and cytokine and eicosanoid production. The optimal therapeutic peptide (peptide 296) contained the lysine-rich region of domain V. In addition, damage and most inflammation were also blocked by peptide 305, which overlaps with peptide 296 but does not contain the lysine- rich, phospholipid-binding region. Importantly, peptide 296 retained efficacy after replacement of cysteine residues with serine. In 2/2 addition, infusion of wild-type serum containing reduced levels of anti–b2-GPI Abs into Rag-1 mice prevented IR-induced http://www.jimmunol.org/ intestinal damage and inflammation. Taken together, these data suggest that the serum protein b2-GPI initiates the IR-induced intestinal damage and inflammatory response and as such is a critical therapeutic target for IR-induced damage and inflamma- tion. The Journal of Immunology, 2010, 185: 6168–6178. uring an ischemic event, the lack of blood flow to an organ activation products prevented both local and remote organ injury induces tissue damage. However, return of blood flow in response to intestinal IR (10–13). D during reperfusion enhances pathology significantly. The Cells subjected to hypoxic conditions express cryptic Ags on inflammatory response to ischemia/reperfusion (IR)-induced organ the plasma membrane (14, 15). Cryptic Ags expressed on apoptotic damage may subsequently lead to a systemic inflammatory response cells are recognized by natural Abs, which frequently exhibit low- by guest on September 27, 2021 with multiple organ failure. Intestinal IR results in severe inflam- affinity binding (16). Previous studies indicated that administer- matory-induced mucosal damage, barrier dysfunction, and sub- ing naturally occurring mAbs reconstituted IR-induced intestinal sequent bacterial translocation leading to sepsis (1) and frequently damage in Ab-deficient Rag-12/2 mice (15, 17–19). Multiple results in liver and lung damage (2). natural Abs, which recognized intracellular Ags, DNA, nonmus- Mesenteric IR-induced tissue injury is mediated by at least cle myosin and ribonucleoprotein, and cardiolipin-induced dam- two components of the innate immune response, neutrophil in- age in the IR-resistant Rag-12/2 mouse, suggesting that the Abs filtration, and complement activation (3–5). Initial studies demon- and Ags are critical to IR-induced damage (18–21). In conjunc- strated that neutrophil depletion attenuated intestinal IR-induced tion with anti-phospholipid mAb, Abs to the serum protein, b2- injury (4, 5). However, the presence of neutrophils was not sufficient glycoprotein I (b2-GPI) also restored tissue damage in Rag-12/2, for tissue damage when complement activation was inhibited (6). IR-resistant mice (19). These data suggest that ischemia induces Complement activation increased adhesion molecule expression a cellular response resulting in expression of multiple cryptic Ags after IR and released a cascade of inflammatory mediators including targeted by low-affinity, naturally occurring Abs also found in au- leukotriene B4 (LTB4) and PGE2, which also contributed to tissue toimmune diseases. damage (7–9). In addition, depletion or inhibition of complement The serum protein b2-GPI, also known as apolipoprotein H, is a member of the complement control protein family (22, 23) but has no known complement regulating function (24). However, b2-GPI *Division of Biology, †College of Veterinary Medicine, and ‡Department of Bio- is a cofactor for plasminogen activation (25) and an opsonin for the chemistry, Kansas State University, Manhattan, KS 66506 clearance of apoptotic cells by phagocytes (26). By binding to an- Received for publication July 28, 2010. Accepted for publication September 15, ionic phospholipids, DNA, or other negatively charged molecules 2010. (22), b2-GPI is the major antigenic target for anti-phospholipid This work was supported by National Institutes of Health Grants AI061691, P20 Abs found in the serum of anti-phospholipid Ab syndrome (APLS) RR017686, and RR016475 from the Institutional Development Award Program of the National Center for Research Resources and Kansas State University. patients (27). Increased anti–b2-GPI Ab titer also correlated with Address correspondence and reprint requests to Dr. Sherry D. Fleming, 18 Ackert increased risk of ischemic stroke or heart disease in APLS or sys- Hall, Kansas State University, Manhattan, KS 66506. E-mail address: sdflemin@ksu. temic lupus erythematosus patients, respectively (28, 29). Taken edu together, these data suggest anti–b2-GPI Abs are involved in is- b b Abbreviations used in this paper: APLS, anti-phospholipid Ab syndrome; 2-GPI, 2- chemic events. glycoprotein I; IR, ischemia/reperfusion; LTB , leukotriene B . 4 4 Based on these data, we hypothesized that during reperfusion, Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 serum protein b2-GPI binds ischemic cell membranes and is www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002520 The Journal of Immunology 6169 recognized by naturally occurring Abs, which leads to complement graded on a six-tiered scale adapted from Chiu et al. (35) as described activation and inflammation. Using an in vitro model, our findings previously (36). Briefly, the average damage score of the intestinal section demonstrate that anti–b2-GPI Abs recognized b2-GPI bound to the (75–150 villi) was determined after grading each villus from 0 to 6. Normal villi were assigned a score of 0; villi with tip distortion were assigned a score surface of hypoxic endothelial cells. In a mouse model of intestinal of 1; a score of 2 was assigned when Guggenheims’ spaces were present; ischemia, b2-GPI binding to damaged ischemic intestinal tissue villi with patchy disruption of the epithelial cells were assigned a score of correlated with tissue injury, and reduction of anti–b2-GPI Abs 3; a score of 4 was assigned to villi with exposed but intact lamina propria mitigated intestinal damage and inflammation. As reduction of Abs with epithelial sloughing; a score of 5 was assigned when the lamina propria b was exuding; and villi that displayed hemorrhage or were denuded were in vivo is difficult, we injected 2-GPI peptides to compete with assigned a score of 6. Photomicrographs were obtained from H&E-stained b2-GPI binding to the tissue. Importantly, injection of peptides slides using a 320, 0.5 Plan Fluor objective on Nikon 80i microscope specific for the lipid-binding domain of b2-GPI blocked intestinal (Nikon, Melville, NY), and images were acquired at room temperature using injury as well as eicosanoid and cytokine production. Administra- a Nikon DS-5M camera with DS-L2 software. tion of peptides containing the phospholipid-binding, lysine-rich Ex vivo eicosanoid and cytokine generation region, and adjacent regions were most effective. Taken together, these data suggest that b2-GPI initiates the IR-induced intestinal Ex vivo generation
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