The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis.
Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model. We found that, unexpectedly, EAE was less severe in Rai(-/-) mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai(+/+) mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis.
Department of Life Sciences, University of Siena, 2 53100, Siena, Italy; cosima.baldari@unisi.it cristina.ulivieri@unisi.it.
Cristina
C
Ulivieri
Department of Life Sciences, University of Siena, 2 53100, Siena, Italy;
Maria Teresa
MT
Savino
Department of Neurosciences, 6 50134 Florence, Italy;
Ilaria
I
Luccarini
Department of Life Sciences, University of Siena, 2 53100, Siena, Italy;
Emanuela
0000-0002-6308-5780
E
Fanigliulo
Department of Neurosciences, 6 50134 Florence, Italy;
Alessandra
0000-0003-4556-913X
A
Aldinucci
Department of Neurosciences, 6 50134 Florence, Italy;
Elena
E
Bonechi
Department of Experimental and Clinical Medicine, University of Florence, 3 50134 Florence, Italy; and.
Marisa
M
Benagiano
Department of Experimental Oncology, European Institute of Oncology, 16 20139 Milan, Italy.
Barbara
0000-0001-7296-670X
B
Ortensi
Department of Experimental Oncology, European Institute of Oncology, 16 20139 Milan, Italy.
Giuliana
G
Pelicci
Department of Experimental and Clinical Medicine, University of Florence, 3 50134 Florence, Italy; and.
Mario Milco
MM
D'Elios
Department of Neurosciences, 6 50134 Florence, Italy;
Clara
0000-0002-7812-9029
C
Ballerini
Department of Life Sciences, University of Siena, 2 53100, Siena, Italy; cosima.baldari@unisi.it cristina.ulivieri@unisi.it.
Cosima Tatiana
0000-0002-4414-6744
CT
Baldari
D000818:Animals; D001253:Astrocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005434:Flow Cytometry; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3 / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
C485682:Shc3 protein, mouse; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3