Role of the PKM2 enzyme in the regulation of the immune and metabolic responses of keratinocytes in an experimental model of skin transplantation

• Grant number: 20/04430-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2020
• End date: April 30, 2024
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Daniel Marconi Mendes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology, AP.TEM
• Associated scholarship(s): 21/13641-0 - Assessment of the PKM2 enzyme as a target for immune modulation during rejection responses in vascularized composite allografts, BE.EP.DD

Abstract

The skin is the largest organ in the body, being responsible for protection against external agents that may be harmful to health. Its outermost layer, called the epidermis, is composed mainly of keratinocytes, primordial cells in the constitution of the epithelial barrier and communication with the immune system, being essential for the efficient repair and healing of the skin when it is injured. However, when such injury occurs profoundly and/or extensively, transplantation of skin grafts are necessary to assist in tissue repair. Due to the high rate of vascularization in the dermis, skin allografts are quickly rejected by the host's immune system, because of that immunosuppressive drugs are used to prevent or delay the rejection process. However, the use of such drugs has negative consequences for the host, therefore, a greater understanding of the mechanisms involved in the rejection of these grafts is essential to increase their survival. Recently, it has been shown that during immune and repair responses, keratinocytes acquire a glycolytic metabolic profile even in the presence of oxygen ("aerobic glycolysis" or Warburg effect). This process depends on the action of the PKM2 enzyme that acts in the last stage of glycolysis and also on the transcription of genes associated with the Warburg effect, thus guaranteeing energy and biomolecules for the production of macromolecules and cell proliferation, fundamental processes for the immune response. and tissue repair. Thus, considering the role of keratinocytes in the repair of skin lesions through cell proliferation and interaction with the immune system, the hypothesis formulated was that the metabolic regulation of keratinocytes promoted by the enzyme PKM2 would imply a phenotypic and functional change that would impact the process of tissue healing in skin transplants through the modulation of the immune system response. Thus, this work aims to study the metabolic and inflammatory profile of keratinocytes in a model of skin transplantation in animals deficient or not for the PKM2 enzyme. It is expected to demonstrate that the acceptance of a transplanted skin involves active metabolic and immunological processes in keratinocytes, thus enabling the discovery of new therapeutic targets that increase the survival of transplanted grafts. (AU)