The CXCR4/CXCL12 (SDF-1) signalling pathway protects non-obese diabetic mouse from autoimmune diabetes.
Chemokines and their receptors are part of polarized T helper 1 (Th1)- and Th2-mediated immune responses which control trafficking of immunogenic cells to sites of inflammation. The chemokine stromal cell-derived factor-1 CXCL-12 (SDF-1) and its ligand the CXCR4 chemokine receptor are important regulatory elements. CXCR4 is expressed on the surface of CD4(+) T cells, dendritic cells and B lymphocytes. Levels of CXCR4 mRNA were increased in pancreatic lymph nodes (PLNs) of 4-week-old non-obese diabetic (NOD) mice in comparison to Balb/C mice. However, a significant reduction of CXCR4 was noticed at 12 weeks both at the mRNA and protein levels while expression increased in the inflamed islets. The percentage of SDF-1 attracted splenocytes in a transwell chemotaxis assay was significantly increased in NOD versus Balb/c mice. SDF-1 attracted T cells completely abolished the capacity of diabetogenic T cells to transfer diabetes in the recipients of an adoptive cell co-transfer. When T splenocytes from NOD females treated with AMD3100, a specific CXCR4 antagonist, were mixed with diabetogenic T cells during adoptive cell co-transfer experiments, prevalence of diabetes in the recipients rose from 33% to 75% (P < 0.001). This effect was associated with an increase of interferon (IFN)-gamma mRNA and a reduction of interleukin (IL)-4 mRNA levels both in PLNs and isolated islets. AMD3100 also reduced IL-4 and IL-10 production of plate-bound anti-CD3 and anti-CD28-stimulated splenocytes. Immunofluorescence studies indicated that AMD3100 reduced the number of CXCR4(+) and SDF-1 positive cells in the inflamed islets. We can conclude that the CXCL-12/CXCR4 pathway has protective effects against autoimmune diabetes.
Aboumrad
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E
INSERM 449, Faculté Laennec, Lyon, France.
Madec
A M
AM
Thivolet
C
C
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000517:prevention & control; D001596:Benzylamines; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000080027:Cyclams; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D012333:RNA, Messenger / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D001596:Benzylamines; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D016207:Cytokines; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C088327:plerixafor