Role of Erk5 pathway on Th17 and Treg cells differentiation and on experimental autoimmune encephalomyelitis

Abstract

T regulatory (Tregs) and T helper 17 (Th17) cells have distinct roles on autoimmune diseases development. Tregs are responsible for controlling homeostasis and immune tolerance, while Th17 cells are self-reactive lymphocytes that orchestrate tissue injury. Thereby, modulation on Treg and Th17 cells is a critical target on new therapeutic approaches development. ERK5 (Extracellular-signal-regulated kinase 5), an atypical member from mitogen-activated protein kinases (MAPK) proteins family, modulate many cellular process, as cellular proliferation, differentiation and survival. One of its unusual features is that in addition to the kinase function, it also acts as scaffold protein, transcription factor or cofactor. Furthermore, it is important on SMRT inhibition, which is a corepressor of PPAR³ receptor that modulates T cell fate destiny to Treg or Th17. Importantly, TGF-², activate ERK5 in kidney epithelial cells, suggesting another evidence of ERK5 role on T cell differentiation. Moreover, it was shown that TGF-² could induce ERK5 phosphorylation in epithelial cells, suggesting another role of this MAPK on T cell differentiation. Nevertheless, there are few data about its role on immune system cells and without data on T cell differentiation and autoimmune diseases development. Thereby, our hypothesis is that ERK5 is activated by TGF-², with consequent activation of PPAR-³ and modulation on Treg/Th17 cell differentiation. Our previous results shown that ERK5 upregultes Treg differentiation and downregulates Th17. Therefore, ERK5 could mediate autoimmune diseases development by Treg/Th17 balance, with great potential to be a new pharmacological target in the development of new therapeutic approaches.