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

• Grant number: 18/25690-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: March 20, 2019
• End date: September 19, 2019
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: Douglas da Silva Prado
• Supervisor: Ari Waisman
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Johannes Gutenberg University Mainz (JGU), Germany
• Associated to the scholarship: 16/05377-3 - Role of Erk5 pathway on Th17 and Treg cells differentiation and on experimental autoimmune encephalomyelitis, BP.DR

Abstract

T regulatory (Tregs) and T helper 17 (Th17) cells have distinct roles in autoimmune pathology. Th17 cells are the major lymphocyte subset that orchestrates the self-reactive tissue injury, while Treg cells are responsible for suppression of the immune response. Thus, the identification of intracellular signalling pathways that regulate the differentiation of Treg and/or Th17 cells could be potential targets for the development of new therapies for autoimmune diseases. ERK5 (Extracellular-signal-regulated kinase 5), an atypical member from mitogen-activated protein kinases (MAPK) proteins family, modulates many cellular processes, such as cellular proliferation, differentiation and survival. Apart from its protein kinase function, ERK5 also is able to act as scaffold protein and co-transcription factor. It was shown that TGF-² could induce ERK5 phosphorylation in epithelial cells, suggesting that this MAPK can have a role in T cell differentiation. Therefore, we proposed to investigate the role of ERK5 in Treg and Th17 differentiation and in the development of an experimental model of autoimmune disease, in which is been funded by FAPESP. We already demonstrated that ERK5 inhibition or deficiency decreases Treg and increases Th17 cells differentiation. Consequently, ERK5-deficient mice display more severe experimental autoimmune encephalomyelitis (EAE). It has been shown that in cardiomyocytes, a molecule called PGC-1±, which is a transcription factor important for mitochondrial biogenesis, is activated by ERK5. In line, our results shown that activation of PGC-1± increases Treg cells differentiation, while its inhibition leads to reduction of Treg cells differentiation. However, the potential role of ERK5 on the modulation of mitochondrial biogenesis and metabolism in Treg cells remains to be clarified, since the mitochondrial metabolism plays a critical role in Treg cells differentiation. Our data also reveal that ERK5 modulates Treg and Th17 differentiation in later time points, suggesting that ERK5 might also be involved in the regulation of Treg/Th17 stability. Therefore, we intend to investigate the role of ERK5 on function/stability and metabolic profile of Treg and Th17 cells. Moreover, another aim is to investigate the role of ERK5 in EAE development using the passive model with transference encephalitogenic 2D2 CD4 T cells. In order to reach these aims, we have set up a collaborative study with Prof. Ari Waisman from Institute for Molecular Medicine, University of Mainz in Germany, which is expert in the field of T cell immunobiology and neuroinflammation. To this end, we are applying for the BEPE fellowship program to spend 6 months in his laboratory to develop this project.