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Stromal Cell–Derived Factor-1/CXCL12 Stimulates Chemorepulsion of NOD/Ltj T-Cell Adhesion to Islet Microvascular Endothelium Christopher D

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Stromal Cell–Derived Factor-1/CXCL12 Stimulates Chemorepulsion of NOD/Ltj T-Cell Adhesion to Islet Microvascular Endothelium Christopher D ORIGINAL ARTICLE Stromal Cell–Derived Factor-1/CXCL12 Stimulates Chemorepulsion of NOD/LtJ T-Cell Adhesion to Islet Microvascular Endothelium Christopher D. Sharp,1 Meng Huang,1 John Glawe,1 D. Ross Patrick,1 Sible Pardue,1 Shayne C. Barlow,2 and Christopher G. Kevil1 OBJECTIVE—Diabetogenic T-cell recruitment into pancreatic islets faciltates ␤-cell destruction during autoimmune diabetes, yet specific mechanisms governing this process are poorly un- iabetogenic T-cell infiltration into pancreatic derstood. The chemokine stromal cell–derived factor-1 (SDF-1) islets is a key pathophysiological feature of controls T-cell recruitment, and genetic polymorphisms of SDF-1 autoimmune diabetes. Recruitment of autoreac- are associated with early development of type 1 diabetes. tive T-cells into islets, known as insulitis, ini- D ␤ tiates the process of -cell damage, which may occur over RESEARCH DESIGN AND METHODS—Here, we examined a protracted period of time, eventually leading to frank the role of SDF-1 regulation of diabetogenic T-cell adhesion to ␤ islet microvascular endothelium. Islet microvascular endothelial destruction of -cells and loss of insulin production (1,2). cell monolayers were activated with tumor necrosis factor-␣ Cellular and molecular mechanisms necessary for recruit- (TNF-␣), subsequently coated with varying concentrations of ment and homing of diabetogenic T-cells have been pur- SDF-1 (1–100 ng/ml), and assayed for T-cell/endothelial cell posed, with antigen presentation and changes in adhesion interactions under physiological flow conditions. molecule expression playing important roles in this pro- cess (3–6). However, T-cell recruitment is regulated by RESULTS—TNF-␣ significantly increased NOD/LtJ T-cell adhe- other factors besides antigen presentation and adhesion sion, which was completely blocked by SDF-1 in a dose-depen- molecule expression. Recent studies have revealed that dent manner, revealing a novel chemorepulsive effect. chemokines serve critically important roles in properly Conversely, SDF-1 enhanced C57BL/6J T-cell adhesion to TNF- ␣ directing T-cell adhesion and migration, which are neces- –activated islet endothelium, demonstrating that SDF-1 aug- sary for immune cell surveillance and recruitment to ments normal T-cell adhesion. SDF-1 chemorepulsion of NOD/ ␣ discreet tissue compartments (7,8). Given the immunolog- LtJ T-cell adhesion was completely reversed by blocking Gi - protein–coupled receptor activity with pertussis toxin. CXCR4 ical importance of these molecules, no information exists protein expression was significantly decreased in NOD/LtJ T- regarding the manner in which chemokine activity con- cells, and inhibition of CXCR4 activity significantly reversed trols diabetogenic T-cell adhesion and recruitment to islet SDF-1 chemorepulsive effects. Interestingly, SDF-1 treatment microvascular endothelium. significantly abolished T-cell resistance to shear-mediated de- The process of T-cell recruitment involves a dynamic tachment without altering adhesion molecule expression, thus series of events involving cell capture, rolling, firm adhe- demonstrating decreased integrin affinity and avidity. sion, and emigration ultimately resulting in T-cell move- ment into the extravascular tissue. Multiple leukocyte and CONCLUSIONS—In this study, we have identified a previously endothelial cell adhesion molecules orchestrate this event unknown novel function of SDF-1 in negatively regulating NOD/ with selectins regulating cell capture and rolling and LtJ diabetogenic T-cell adhesion, which may be important in integrins regulating T-cell firm adhesion and transmigra- regulating diabetogenic T-cell recruitment into islets. Diabetes 57:102–112, 2008 tion (9–11). Distinct cellular responses accompany the transition of T-cell recruitment from one phase to the next with chemokine receptor interactions serving to activate signaling pathways necessary for firm adhesion. Chemo- From the 1Department of Pathology, Louisiana State University Health Sci- kines are small heparin-binding proteins that have been ences Center, Shreveport, Louisiana; and the 2Department of Pharmacology, defined based on amino acid composition of conserved Physiology and Neuroscience, University of South Carolina, Columbia, South tetra-cysteine motifs, resulting in two major subclasses, Carolina. Address correspondence and reprint requests to Christopher Kevil, PhD, CXC (separation by a nonconserved amino acid) or CC Department of Pathology, Louisiana State University Health Sciences Center- (adjacent cysteine location), along with three other homol- Shreveport, 1501 Kings Hwy., Shreveport, LA 71130-3932. E-mail: ckevil@ ogous molecules of differing motifs (12). Numerous che- lsuhsc.edu. Received for publication 11 May 2007 and accepted in revised form 26 mokines have been identified to date that bind to various September 2007. receptors in redundant fashion. Chemokine receptors are Published ahead of print at http://diabetes.diabetesjournals.org on 1 Octo- surface G-protein–coupled receptors that contain seven ber 2007. DOI: 10.2337/db07-0494. C.D.S. and M.H. contributed equally to this work. membrane-spanning domains that activate downstream FACS, fluorescence-activated cell sorting; GST, glutathione S-transferase; G-protein signal cascades. Chemokines avidly bind glycos- HBSS, Hanks’ balanced salt solution; ICAM-1, intracellular adhesion mole- aminoglycans associated with cells or matrix proteins and cule-1; NIH, National Institutes of Health; PMSF, phenylmethylsulfonyl fluo- are readily diffusible because of their small size (7–15 ride; SDF-1, stromal cell–derived factor-1; TBS, Tris-buffered saline; TNF-␣, tumor necrosis factor-␣; VCAM-1, vascular cell adhesion molecule-1. kDa). Moreover, chemokines may also be transported © 2008 by the American Diabetes Association. through or around microvascular endothelium, thus fur- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance ther identifying discreet regions for leukocyte recruitment with 18 U.S.C. Section 1734 solely to indicate this fact. (13). Together, these structural and biochemical features 102 DIABETES, VOL. 57, JANUARY 2008 C.D. SHARP AND ASSOCIATES contribute to the strong ability of chemokines to control velocity. Firmly adherent cells were defined as those that did not move one directional leukocyte recruitment and migration. cell diameter over a 5-s period as determined by automated tracking and manual review of individual cells in each experimental field of view. Chemokines can facilitate leukocyte recruitment and ϩ Western blot analysis. CD3 cells were isolated as described above. Cells migration through alterations of adhesion molecule func- were rinsed in Tris-buffered saline (TBS) and spun for 5 min at 1,500 rpm. The tion or cellular location. Chemokine stimulation facilitates resulting pellet was lysed in radioimmunoprecipitation assay buffer (50 mmol/l integrin-mediated adhesion by altering the state of integrin Tris-HCL, pH 8.0, 150 mmol/l NaCl, 1% Nonidet-40, 0.5% deoxycholate, and activation by converting it from a “closed” nonbinding 0.1% SDS) supplemented with 0.1 ␮mol/l leupeptin, 0.3 ␮mol/l aprotinin, and state to an “open” high binding state, thereby increasing 1 ␮mol/l phenylmethylsulfonyl fluoride (PMSF). Samples were sonicated for affinity for ligand or altering integrin cell surface location three 5-s intervals on ice. Protein determination was preformed using a into discreet clusters and, thus, enhancing avidity for Bio-Rad DC Protein kit (Bio-Rad, Hercules, CA) according to the manufactur- er’s instructions. Whole-cell protein homogenates (25 ␮g total protein) were ligand (14). Both of these molecular events may occur loaded on 12% polyacrylamide SDS gels, and electrophoresis was performed simultaneously, providing a very rapid and effective re- as we have previously reported (23). Gels were transferred overnight to sponse to enhance leukocyte adhesion. The chemokine Immobilon-P7 (Bio-Rad), and subsequent membranes were blocked with 5% stromal cell–derived factor-1 (SDF-1)/CXCL12 has been BSA in TBS for 2 h. Anti-CXCR4 antibody (E-Bioscience, San Diego, CA) was reported to rapidly stimulate integrin-dependent T-cell incubated overnight at 1:1,000 dilution at 4°C in blocking buffer supplemented firm adhesion under hydrodynamic flow conditions, which with 0.1% polyoxyethylenesorbitan monolaurate (Tween-20). The remaining involves changes in integrin affinity or avidity in a G- washes and incubations were performed at room temperature in TBS con- protein–coupled receptor-dependent manner (15–17). In- taining 0.1% milk and 0.1% Tween-20. Membranes were washed three times for 5 min and allowed to incubate with the peroxidase secondary anti-rabbit terestingly, recent reports suggest that polymorphisms of antibody for 2 h. After three 10-min washes, membranes were rinsed for 10 SDF-1/CXCL12 may be associated with the early develop- min in TBS alone. Chemiluminesence was preformed using ECL detection ment of autoimmune diabetes, yet the effects of SDF-1 on reagents (Amersham, Piscataway, NJ) according to the manufacturer’s direc- regulating diabetogenic T-cell adhesion are completely tions. Various exposures to Hyblot film (Denville Scientific, Metuchen, NJ) unknown (18,19). In this study, we examined the effect of were performed to insure exposure linearity. Films were scanned and SDF-1 on NOD/LtJ diabetogenic T-cell adhesion to acti- quantified using Image
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