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

Current Diabetes Reports

Volumn 15, Issue 10, 2015, Pages

  Citro, Antonio ^a   Cantarelli, Elisa ^a   Piemonti, Lorenzo ^a  

^a SAN RAFFAELE HOSPITAL   (Italy)

Author keywords

Chemokine; Chemokine receptor; CXCR1 2; Neutrophils; Pancreatic islets; Type 1 diabetes

Indexed keywords

1 (2 BROMOPHENYL) 3 (2 HYDROXY 4 NITROPHENYL)UREA; AZD 8309; CHEMOKINE RECEPTOR CXCR1; CHEMOKINE RECEPTOR CXCR2; CHEMOKINE RECEPTOR CXCR2 ANTAGONIST; LADARIXIN; N [2 (2,3 DIFLUOROBENZYLTHIO) 6 (2,3 DIHYDROXY 1 METHYLPROPOXY) 4 PYRIMIDINYL] 1 AZETIDINESULFONAMIDE; NAVARIXIN; NEUTRALIZING ANTIBODY; PEPDUCIN; PROTEIN INHIBITOR; REPARIXIN; UNCLASSIFIED DRUG;

ASTHMA; AUTOIMMUNE DISEASE; AUTOIMMUNITY; BREAST CANCER; CELL DAMAGE; CHRONIC OBSTRUCTIVE LUNG DISEASE; COLORECTAL CANCER; DIABETES MELLITUS; DIABETOGENESIS; DISEASE COURSE; DRUG MECHANISM; HUMAN; IMMUNOPATHOGENESIS; INFLAMMATORY DISEASE; INNATE IMMUNITY; INSULIN DEPENDENT DIABETES MELLITUS; INSULITIS; LEUKOCYTE MIGRATION; LIVER METASTASIS; LUNG CANCER; LYMPHOID CELL; MACROPHAGE; NEUTROPHIL; NONHUMAN; PANCREAS ISLET BETA CELL; PATHOPHYSIOLOGY; PRIMARY TUMOR; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN TARGETING; RECEPTOR BLOCKING; REPERFUSION INJURY; REVIEW; RHEUMATOID ARTHRITIS; ANIMAL; DIABETES MELLITUS, TYPE 1; IMMUNOLOGY; METABOLISM; PANCREAS ISLET; SIGNAL TRANSDUCTION;

ANIMALS; DIABETES MELLITUS, TYPE 1; HUMANS; ISLETS OF LANGERHANS; NEUTROPHILS; RECEPTORS, INTERLEUKIN-8A; RECEPTORS, INTERLEUKIN-8B; SIGNAL TRANSDUCTION;

EID: 84939130422     PISSN: 15344827     EISSN: 15390829     Source Type: Journal    
DOI: 10.1007/s11892-015-0638-x     Document Type: Review

References (75)

1. Peakman M. Immunological pathways to beta-cell damage in type 1 diabetes. Diabet Med. 2013;30(2):147–54.
2. Lehuen A et al. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10(7):501–13.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
17. Citro A, Cantarelli E, Piemonti L. Anti-inflammatory strategies to enhance islet engraftment and survival. Curr Diab Rep. 2013;13(5):733–44.
18. Melzi R et al. Role of CCL2/MCP-1 in islet transplantation. Cell Transplant. 2010;19(8):1031–46.
19. Murphy PM. Neutrophil receptors for interleukin-8 and related CXC chemokines. Semin Hematol. 1997;34(4):311–8.
20. Lee J et al. Characterization of two high affinity human interleukin-8 receptors. J Biol Chem. 1992;267(23):16283–7.
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.
22. Kelvin DJ et al. Chemokines and serpentines: the molecular biology of chemokine receptors. J Leukoc Biol. 1993;54(6):604–12.
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.
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.
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.
26. Lee J et al. Chemokine binding and activities mediated by the mouse IL-8 receptor. J Immunol. 1995;155(4):2158–64.
27. Murphy PM. The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol. 1994;12:593–633.
28. Hoffmann E et al. Multiple control of interleukin-8 gene expression. J Leukoc Biol. 2002;72(5):847–55.
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.
30. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4(7):540–50.
31. Dwyer MP, Yu Y. CXCR2 receptor antagonists: a medicinal chemistry perspective. Curr Top Med Chem. 2014;14(13):1590–605.
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.
33. Sanz MJ, Kubes P. Neutrophil-active chemokines in in vivo imaging of neutrophil trafficking. Eur J Immunol. 2012;42(2):278–83.
34. Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity. 2014;41(5):694–707.
35. Eltzschig HK, Eckle T. Ischemia and reperfusion–from mechanism to translation. Nat Med. 2011;17(11):1391–401.
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.
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.
38. Seitz M et al. Enhanced production of neutrophil-activating peptide-1/interleukin-8 in rheumatoid arthritis. J Clin Invest. 1991;87(2):463–9.
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.
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.
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.
42. Belperio JA et al. CXCR2/CXCR2 ligand biology during lung transplant ischemia-reperfusion injury. J Immunol. 2005;175(10):6931–9.
43. de Boer WI. Cytokines and therapy in copd*: a promising combination? Chest. 2002;121(5_suppl):209S–18S.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
66. Salchow K et al. A common intracellular allosteric binding site for antagonists of the CXCR2 receptor. Br J Pharmacol. 2010;159(7):1429–39.
67. Gonsiorek W et al. Pharmacological characterization of Sch527123, a potent allosteric CXCR1/CXCR2 antagonist. J Pharmacol Exp Ther. 2007;322(2):477–85.
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.
69. Varney ML et al. Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases. Cancer Lett. 2011;300(2):180–8.
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.
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.
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.
73. Kaneider NC et al. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nat Med. 2005;11(6):661–5.
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.
75. Jamieson T et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J Clin Invest. 2012;122(9):3127–44.