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Current Diabetes Reports
Erschienen in: Current Diabetes Reports 10/2015

01.10.2015 | Immunology and Transplantation (A Pileggi, Section Editor)

The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

verfasst von: Antonio Citro, Elisa Cantarelli, Lorenzo Piemonti

Erschienen in: Current Diabetes Reports | Ausgabe 10/2015

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Abstract

Although numerous chemokine/chemokine receptor pathways have been described to be implicated in the pathogenesis of type 1 diabetes (T1D), the CXCR1/2 axis has recently been proved to be crucial for leucocyte recruitment involved in insulitis and β cell damage. Multiple strategies blocking the CXCR1/2 pathway are available such as neutralizing antibodies, small molecules and peptide-derived inhibitors. They were firstly and widely used in cancer thanks to their anti-tumorigenic activity and only recently they were tested as a new interventional approach for T1D. As well, CXCR1/2 inhibition has been demonstrated to prevent inflammation- and autoimmunity-mediated damage of the pancreatic islets through inhibiting the migration of CXCR1/2-expressing cells. Among them, neutrophils, macrophages, and, although to a smaller extent, lymphoid cells are the main CXCR1/2-expressing cells. These results supported the active role of the innate immunity in the autoimmune process and opened new interventional approaches for the management of T1D.
Literatur
1.
Peakman M. Immunological pathways to beta-cell damage in type 1 diabetes. Diabet Med. 2013;30(2):147–54.PubMedCrossRef
2.
Lehuen A et al. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10(7):501–13.PubMedCrossRef
3.
Turley S et al. Physiological β cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med. 2003;198(10):1527–37.PubMedCentralPubMedCrossRef
4.•
Valle A et al. Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes. 2013;62(6):2072–7. This paper is the first clinical evidence about the presence of neutrophils in the pancreas of patients affected by T1D.PubMedCentralPubMedCrossRef
5.
Harsunen MH et al. Reduced blood leukocyte and neutrophil numbers in the pathogenesis of type 1 diabetes. Horm Metab Res. 2013;45(6):467–70.PubMedCrossRef
6.
Schneider DA, Kretowicz AM, von Herrath MG. Emerging immune therapies in type 1 diabetes and pancreatic islet transplantation. Diabetes Obes Metab. 2013;15(7):581–92.PubMedCrossRef
7.
Chatenoud L et al. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A. 1994;91(1):123–7.PubMedCentralPubMedCrossRef
8.
Barlow AK, Like AA. Anti-CD2 monoclonal antibodies prevent spontaneous and adoptive transfer of diabetes in the BB/Wor rat. Am J Pathol. 1992;141(5):1043–51.PubMedCentralPubMed
9.
Like AA et al. Spontaneous diabetes mellitus: reversal and prevention in the BB/W rat with antiserum to rat lymphocytes. Science. 1979;206(4425):1421–3.PubMedCrossRef
10.
Grinberg-Bleyer Y et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med. 2010;207(9):1871–8.PubMedCentralPubMedCrossRef
11.
Sumpter KM et al. Preliminary studies related to anti-interleukin-1beta therapy in children with newly diagnosed type 1 diabetes. Pediatr Diabetes. 2011;12(7):656–67.PubMedCrossRef
12.
Mastrandrea L et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care. 2009;32(7):1244–9.PubMedCentralPubMedCrossRef
13.
Buzzetti R et al. C-peptide response and HLA genotypes in subjects with recent-onset type 1 diabetes after immunotherapy with DiaPep277: an exploratory study. Diabetes. 2011;60(11):3067–72.PubMedCentralPubMedCrossRef
14.
Lozanoska-Ochser B et al. Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic beta-cell-specific CD8 T-cells. Diabetes. 2006;55(4):1004–10.PubMedCrossRef
15.
Xue S et al. Exendin-4 treatment of nonobese diabetic mice increases beta-cell proliferation and fractional insulin reactive area. J Diabetes Complicat. 2010;24(3):163–7.PubMedCrossRef
16.
Ding L et al. Combining MK626, a novel DPP-4 inhibitor, and low-dose monoclonal CD3 antibody for stable remission of new-onset diabetes in mice. PLoS One. 2014;9(9):e107935.PubMedCentralPubMedCrossRef
17.
Citro A, Cantarelli E, Piemonti L. Anti-inflammatory strategies to enhance islet engraftment and survival. Curr Diab Rep. 2013;13(5):733–44.PubMedCrossRef
18.
Melzi R et al. Role of CCL2/MCP-1 in islet transplantation. Cell Transplant. 2010;19(8):1031–46.PubMedCrossRef
19.
Murphy PM. Neutrophil receptors for interleukin-8 and related CXC chemokines. Semin Hematol. 1997;34(4):311–8.PubMed
20.
Lee J et al. Characterization of two high affinity human interleukin-8 receptors. J Biol Chem. 1992;267(23):16283–7.PubMed
21.
Loetscher P et al. Both interleukin-8 receptors independently mediate chemotaxis. Jurkat cells transfected with IL-8R1 or IL-8R2 migrate in response to IL-8, GRO alpha and NAP-2. FEBS Lett. 1994;341(2-3):187–92.PubMedCrossRef
22.
Kelvin DJ et al. Chemokines and serpentines: the molecular biology of chemokine receptors. J Leukoc Biol. 1993;54(6):604–12.PubMed
23.
Shuster DE, Kehrli Jr ME, Ackermann MR. Neutrophilia in mice that lack the murine IL-8 receptor homolog. Science. 1995;269(5230):1590–1.PubMedCrossRef
24.
Davatelis G et al. Cloning and characterization of a cDNA for murine macrophage inflammatory protein (MIP), a novel monokine with inflammatory and chemokinetic properties. J Exp Med. 1988;167(6):1939–44.PubMedCrossRef
25.
Oquendo P et al. The platelet-derived growth factor-inducible KC gene encodes a secretory protein related to platelet alpha-granule proteins. J Biol Chem. 1989;264(7):4133–7.PubMed
26.
Lee J et al. Chemokine binding and activities mediated by the mouse IL-8 receptor. J Immunol. 1995;155(4):2158–64.PubMed
27.
Murphy PM. The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol. 1994;12:593–633.PubMedCrossRef
28.
Hoffmann E et al. Multiple control of interleukin-8 gene expression. J Leukoc Biol. 2002;72(5):847–55.PubMed
29.
Zaslaver A, Feniger-Barish R, Ben-Baruch A. Actin filaments are involved in the regulation of trafficking of two closely related chemokine receptors, CXCR1 and CXCR2. J Immunol. 2001;166(2):1272–84.PubMedCrossRef
30.
31.
Dwyer MP, Yu Y. CXCR2 receptor antagonists: a medicinal chemistry perspective. Curr Top Med Chem. 2014;14(13):1590–605.PubMedCrossRef
32.
Pruenster M et al. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nat Immunol. 2009;10(1):101–8.PubMedCentralPubMedCrossRef
33.
Sanz MJ, Kubes P. Neutrophil-active chemokines in in vivo imaging of neutrophil trafficking. Eur J Immunol. 2012;42(2):278–83.PubMedCrossRef
34.
Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity. 2014;41(5):694–707.PubMedCrossRef
35.
Eltzschig HK, Eckle T. Ischemia and reperfusion–from mechanism to translation. Nat Med. 2011;17(11):1391–401.PubMedCrossRef
36.
de Boer WI et al. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J Pathol. 2000;190(5):619–26.PubMedCrossRef
37.
Clunes MT, Boucher RC. Cystic fibrosis: the mechanisms of pathogenesis of an inherited lung disorder. Drug Discov Today Dis Mech. 2007;4(2):63–72.PubMedCentralPubMedCrossRef
38.
39.•
Citro A et al. CXCR1/2 inhibition enhances pancreatic islet survival after transplantation. J Clin Invest. 2012;122(10):3647–51. This study provides for the first time that CXCR1/2 pathway is a master regulator of islet damage and should be a target for intervention to improve the islet survival after transplantation.PubMedCentralPubMedCrossRef
40.
Cugini D et al. Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia//reperfusion. Kidney Int. 2005;67(5):1753–61.PubMedCrossRef
41.
Liehn EA et al. Compartmentalized protective and detrimental effects of endogenous macrophage migration-inhibitory factor mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion. Arterioscler Thromb Vasc Biol. 2013;33(9):2180–6.PubMedCentralPubMedCrossRef
42.
Belperio JA et al. CXCR2/CXCR2 ligand biology during lung transplant ischemia-reperfusion injury. J Immunol. 2005;175(10):6931–9.PubMedCrossRef
43.
de Boer WI. Cytokines and therapy in copd*: a promising combination? Chest. 2002;121(5_suppl):209S–18S.PubMedCrossRef
44.
Qiu Y et al. Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;168(8):968–75.PubMedCrossRef
45.
Ritzman AM et al. The chemokine receptor CXCR2 ligand KC (CXCL1) mediates neutrophil recruitment and is critical for development of experimental Lyme arthritis and carditis. Infect Immun. 2010;78(11):4593–600.PubMedCentralPubMedCrossRef
46.••
Citro A et al. CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice. Diabetes. 2015;64(4):1329–40. This study underlines the relevance of targeting CXCR1/2 pathway in a preclinical model of T1D showing the possibility to block or temporary revert the disease.PubMedCrossRef
47.
Negi S et al. Analysis of beta-cell gene expression reveals inflammatory signaling and evidence of dedifferentiation following human islet isolation and culture. PLoS One. 2012;7(1):e30415.PubMedCentralPubMedCrossRef
48.
Erbagci AB et al. Mediators of inflammation in children with type I diabetes mellitus: cytokines in type I diabetic children. Clin Biochem. 2001;34(8):645–50.PubMedCrossRef
49.
Takahashi K et al. Serum CXCL1 concentrations are elevated in type 1 diabetes mellitus, possibly reflecting activity of anti-islet autoimmune activity. Diabetes Metab Res Rev. 2011;27(8):830–3.PubMedCrossRef
50.
Omatsu T et al. CXCL1/CXCL8 (GROalpha/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro. Am J Physiol Endocrinol Metab. 2014;306(9):E1077–84.PubMedCrossRef
51.
Planas R et al. Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNbeta. Diabetologia. 2006;49(10):2379–87.PubMedCrossRef
52.••
Diana J, Lehuen A. Macrophages and beta-cells are responsible for CXCR2-mediated neutrophil infiltration of the pancreas during autoimmune diabetes. EMBO Mol Med. 2014;6(8):1090–104. The authors suggest the relevance of macrophages and CXCR2-positive neutrophils in the early stage of the pathophysiology of T1D.PubMedCentralPubMedCrossRef
53.••
Diana J et al. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med. 2013;19(1):65–73. This study provides an innovative description of the potential crosstalk between the innate and adaptive response during the progression in a preclinical model of T1D.PubMedCrossRef
54.
Campbell LM, Maxwell PJ, Waugh DJ. Rationale and means to target pro-inflammatory interleukin-8 (CXCL8) signaling in cancer. Pharmaceuticals (Basel). 2013;6(8):929–59.CrossRef
55.
Singh S et al. CXCR1 and CXCR2 silencing modulates CXCL8-dependent endothelial cell proliferation, migration and capillary-like structure formation. Microvasc Res. 2011;82(3):318–25.PubMedCentralPubMedCrossRef
56.
Schraufstatter IU, Chung J, Burger M. IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways. Am J Physiol Lung Cell Mol Physiol. 2001;280(6):L1094–103.PubMed
57.
Sanchez J et al. The role of CXCR2 in systemic neovascularization of the mouse lung. J Appl Physiol (1985). 2007;103(2):594–9.CrossRef
58.
Matsuo Y et al. CXC-chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer. Int J Cancer. 2009;125(5):1027–37.PubMedCrossRef
59.
Bizzarri C et al. ELR+ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets. Pharmacol Ther. 2006;112(1):139–49.PubMedCrossRef
60.
Ginestier C et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest. 2010;120(2):485–97.PubMedCentralPubMedCrossRef
61.
White JR et al. Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration. J Biol Chem. 1998;273(17):10095–8.PubMedCrossRef
62.
Jin Q et al. Discovery of potent and orally bioavailable N, N’-diarylurea antagonists for the CXCR2 chemokine receptor. Bioorg Med Chem Lett. 2004;14(17):4375–8.PubMedCrossRef
63.
Bento AF et al. The selective nonpeptide CXCR2 antagonist SB225002 ameliorates acute experimental colitis in mice. J Leukoc Biol. 2008;84(4):1213–21.PubMedCrossRef
64.
Dwyer MP et al. Discovery of 2-hydroxy-N, N-dimethyl-3-{2-[[(R)-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobut-1-enylamino}benzamide (SCH 527123): a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist. J Med Chem. 2006;49(26):7603–6.PubMedCrossRef
65.
Moss RB et al. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros. 2013;12(3):241–8.PubMedCrossRef
66.
67.
Gonsiorek W et al. Pharmacological characterization of Sch527123, a potent allosteric CXCR1/CXCR2 antagonist. J Pharmacol Exp Ther. 2007;322(2):477–85.PubMedCrossRef
68.
Ning Y et al. The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models. Mol Cancer Ther. 2012;11(6):1353–64.PubMedCrossRef
69.
70.
Holz O et al. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur Respir J. 2010;35(3):564–70.PubMedCrossRef
71.
Virtala R et al. Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor. Clin Exp Allergy. 2012;42(4):590–6.PubMedCrossRef
72.
O’Callaghan K, Kuliopulos A, Covic L. Turning receptors on and off with intracellular pepducins: new insights into G-protein-coupled receptor drug development. J Biol Chem. 2012;287(16):12787–96.PubMedCentralPubMedCrossRef
73.
Kaneider NC et al. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nat Med. 2005;11(6):661–5.PubMedCrossRef
74.
Dimond P et al. G protein-coupled receptor modulation with pepducins: moving closer to the clinic. Ann N Y Acad Sci. 2011;1226:34–49.PubMedCrossRef
75.
Jamieson T et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J Clin Invest. 2012;122(9):3127–44.PubMedCentralPubMedCrossRef
Metadaten
Titel
The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions
verfasst von
Antonio Citro
Elisa Cantarelli
Lorenzo Piemonti
Publikationsdatum
01.10.2015
Verlag
Springer US
Erschienen in
Current Diabetes Reports / Ausgabe 10/2015
Print ISSN: 1534-4827
Elektronische ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-015-0638-x

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