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Scientists discover key enzymes involved in the development of autoimmune diseases

Publicado em 20 outubro 2020

Scientists from the Center for Research on Inflammatory Diseases (CRID http: // crid.fmrp.usp.br), organized by the University of São Paulo (USP) in Brazil, have discovered that an enzyme that is involved in important metabolic processes also plays a role in the differentiation of immune cells and thus in the development of autoimmune diseases. The result could contribute to the future development of new therapies and cheaper and more determined drugs for this type of disease.

The study is reported (https: //.Rupress.org /someoneItems/217 /10 /e20190613 /151965 /PKM2 promotes Th17 cell differentiation and) in the Journal of Experimental Medicine. The article describes the role of PKM2 (pyruvate kinase M2), the enzyme responsible for the final step in glycolysis, in the development and maintenance of the increased inflammation typical of autoimmune diseases. Glycolysis is the breakdown of glucose to generate energy for cell metabolism.

“In the study we showed that there is a connection between cell metabolism and the immune system. It is becoming increasingly clear that enzymes and other metabolic molecules are not only important for cell metabolism, but also for other functions such as the immune response. In this particular one We found that the enzyme PKM2 acts in parallel to the differentiation of Th17, a lymphocyte subtype that causes experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, “said José Carlos Farias Alves Filho (https: //.bv.fapesp.br /de /pesquisador /62548 /jose-carlos-farias-alves-filho), a researcher at CRID, one of several Research, Innovation and Dissemination Centers (RIDCs) (https: //.cepid.fapesp.br /de /home)) supported by the São Paulo Research Foundation – FAPESP. CRID is hosted by the Ribeirão Preto Medical School (FMRP-USP) of the USP.

The study (https: //.bv.fapesp.br /de /bolsas /167614) was researched by Luis Eduardo Alves Damasceno (https: //.bv.fapesp.br /de /pesquisador /689340 /luis-eduardo-alves-damasceno), with a grant from FAPESP and under the supervision of Alves Filho.

T-helper lymphocytes

To specifically neutralize various pathogens, immune cells called T lymphocytes differentiate into a number of subtypes, including T helper type 17 cells (Th17). These are linked to the development and maintenance of inflammation, which is common in autoimmune diseases.

For poorly understood reasons, autoimmune diseases such as multiple sclerosis, arthritis and psoriasis can cause the immune response to get out of hand and cause T lymphocytes to attack their own organism as if it were a pathogen.

For his project, Damasceno used the model known as experimental immune encephalomyelitis, an inflammatory demyelinating disease of the central nervous system that results in the loss of the myelin sheath and protects nerve fibers and allows electrical impulses to travel along them quickly and efficiently. The experimental model is very similar to the condition of patients with multiple sclerosis.

It has long been known that Th17 cells play a key role in mediating the development of autoimmune diseases and the progression of neuroinflammation typical of several autoimmune diseases. The initial auto-reactive response that triggers the disease occurs when Th17 cells believe antigens in the central nervous system to be a threat and release large amounts of an inflammatory protein called interleukin 17 (IL-17) into lesions of the spinal cord and brain tissue.

In the study using cultured cells and the animal model, the CRID researchers found that the differentiation of T lymphocytes into Th17 cells and the development of the disease was dependent on metabolic reprogramming and changes in glycolysis.

The glycolytic enzyme pyruvate kinase M2 [PKM2] mediated Th17 differentiation and autoimmune inflammation. We have shown in the study that significant amounts of the enzyme are expressed during the differentiation of T lymphocytes in Th17 cells. “

Farias Alves Filho, researcher at CRID

When T-cell specific PKM2 was excluded in vitro, Th17 differentiation was impaired and disease symptoms were attenuated, thereby reducing Th17-mediated inflammation and demyelination. “In the tests with mice that were modified so that they did not express the enzyme, the development of the disease was reduced by over 50%,” said Alves Filho. The researchers also analyzed the use of commercial drugs that inhibit PKM2. “We used a drug that inhibits the nuclear translocation of PKM2 so that the enzyme does not reach the nucleus. The lymphocytes express the enzyme but do not affect the development of the disease. It is reduced because the Th17 differentiation decreases,” said he said.

Treatment costs and benefits

The discovery of the role of PKM2 in autoimmune diseases paves the way for the development of new strategies for their treatment. The immunosuppressants currently available on the market treat these diseases by inhibiting the cytokines that help activate and differentiate between the various lymphocyte subtypes.

“An estimated 40% of patients do not respond well to these drugs for one reason or another,” said Alves Filho. “They could be treated with immunobiological drugs that are very beneficial but extremely expensive and unaffordable for many patients.”

The enzyme is part of CRID’s drug discovery platform. “In the study, we used a commercial drug that targets an allosteric site of PKM2 and blocks the enzyme’s ability to move to the Th17 nucleus,” he said. In collaboration with the Bioscience National Laboratory (LNBio) of the Brazilian Center for Energy and Materials Research (CNPEM) in Campinas, State of São Paulo, a new study has begun to develop drugs that target the translocation of the enzyme.

“This opens the prospect of novel treatments for autoimmune or inflammatory diseases that depend on this enzyme,” said Alves Filho. “In this next phase, we want to develop drugs that interact with this site and inhibit the ability of the enzyme to move to the nucleus.”

Source:

Research Foundation São Paulo (FAPESP)

Journal reference:

Alves Damasceno, LE, et al. (2020) PKM2 Promotes Th17 Cell Differentiation and Autoimmune Inflammation by Fine-Tuning STAT3 Activation. Journal of Experimental Medicine. doi.org/10.1084/jem.20190613.

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