Role of the ERK5-dependent signaling pathway in the differentiation of Th17 and Treg cells and in the development of experimental autoimmune encephalomyelitis

ERK5 (extracellular-signal-regulated kinase 5) is an atypical member of MAPK family, because it works as a kinase and can also regulate transcription factor activity by protein- protein interaction, which it happens in an independent way of your kinase function. Interestingly, ERK5 is activated in different cell types by TGF-β, which modulates Treg and Th17 cell differentiation. These two CD4 T cells subtypes are responsible for modulating the development of autoimmune diseases. Thus, while Treg cells control homeostasis and maintenance of immune tolerance, Th17 cells are self-reactive effector cells that orchestrate tissue damage. In addition, ERK5 also could be activated by TGF-β in T lymphocytes Treg and Th17 and then would modulate the differentiation of these cells, which are important for the development of a mouse model of autoimmune disease, called EAE, (experimental autoimmune encephalomyelitis). Thus, the role of ERK5 on Treg and Th17 differentiation, as well as the role of TGF-β on ERK5 activation and effects were performed by naive CD4 T cells culture. Furthermore, it was investigated the function of ERK5 on EAE model, which was induced by an injection of an emulsion containing MOG35-55. In this study, we have shown that TGF-β induced ERK5 phosphorylation in Treg and Th17 cells. Moreover, ERK5 inhibition or deletion reduced Treg and increased Th17 differentiation. Strikingly, this process was not dependent of MEK5 signaling or ERK5 kinase activity. On the other hand, the cytokine TGF-β mediated ERK5 effects, as well its nuclear translocation. Thus, our data suggest that ERK5 nuclear localization is important to its function on Treg and Th17 differentiation. Finally, ERK5-deficient mice displayed more severe EAE, which was associated with lower Treg frequency and higher Th17. Therefore, this study has shown a new role of ERK5 on Treg and Th17 differentiation and in the EAE development, suggesting that ERK5 could be a possible pharmacological target to the development of new therapies for the treatment of autoimmune diseases. (AU)