The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis

Abstract

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.

3D Organotypic Spinal Cultures: Exploring Neuron and Neuroglia Responses Upon Prolonged Exposure to Graphene Oxide

“…Interestingly, the cytokines and chemokines profiles measured in organotypic cultures supernatant, although slightly altered, were not significantly increased after 2 weeks of s-GO exposure. In this regard, we did not find an increase in IL-6, that is produced by astrocyte following, for example, a proinflammatory stimulation (Ulivieri et al, 2016). Therefore, in this model, we may hypothesize that microglial proliferative response with no significant variation in cytokines production after 2 weeks, does not involve a shift into the M1 phenotype.…”

A T Cell Suppressive Circuitry Mediated by CD39 and Regulated by ShcC/Rai Is Induced in Astrocytes by Encephalitogenic T Cells

“…Although astrocyte conversion to the A1 phenotype has been shown to be modulated by activated microglia in human neurodegenerative diseases including multiple sclerosis (11), the underlying mechanism and the impact of encephalitogenic T cells on this process remain unknown. Our data provide evidence for a new role of Rai as a negative regulator of astrocyte polarization to the A2 phenotype, highlighting an additional mechanism involving astrocytes that contributes to attenuating EAE severity in Rai −/− mice (23).…”

“…This results both from the enhanced ability of Rai −/− astrocytes to degrade eATP to adenosine in response to short-term IFNγ treatment and from the greater increase in CD39 expression and frequency of the CD39 + CD73 + subpopulation after long-term IFNγ treatment compared to their wild-type counterparts. These results provide insights into the mechanisms responsible for the protective effect of Rai deficiency in astrocytes from encephalitogenic T cell-dependent neurodegeneration (23). Rai was initially identified as a molecular adaptor that couples the receptor tyrosine kinase Ret to Akt in neuronal cells (52).…”

“…with 300 ng B. pertussis toxin (Calbiochem, Darmstadt, Germany). Mice were monitored daily by two independent researchers and clinical scores were assigned according to the standard 0 to 5 scale (23, 26). Brain and spinal cords were isolated from EAE mice (15 days post-immunization) and total glial cells were obtained as described (23).…”

“…We have recently reported that deficiency of ShcC/Rai, a member of the Shc family of protein adaptors, protects mice from demyelination and prevents reactive astrogliosis during EAE notwithstanding enhanced CNS infiltration by encephalitogenic Th17 cells, due to reduced astrocytic production of pro-inflammatory molecules in response to T cell-derived factors (23). Here we have addressed the outcome of Rai deficiency on the ability of astrocytes to generate a T cell suppressive microenvironment through eATP degradation.…”