Role of neutrophil extracellular traps on the production of resolution mediators in bone loss

• Grant number: 22/13018-4
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): May 01, 2023
• Effective date (End): April 30, 2024
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Ayda Henriques Schneider
• Supervisor: Mauro Perretti
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: Queen Mary University of London, England
• Associated to the scholarship: 19/19190-0 - Role of NETs as osteoclastogenesis modulators in Rheumatoid Arthritis , BP.DR

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that affects 0.5 to 1% of adult world population, and it is characterized by bone loss. Osteoblasts are bone cells that synthetize bone matrix and stimulate osteoclasts, that degrade which in turn degrade matrix, though the release of the receptor activator of nuclear factor ºB ligand (RANKL), that interacts with its receptor (RANK) on the osteoclast's precursors (monocytes), generating osteoclasts, process known as osteoclastogenesis. Wheres this process occurs physiologically and is coherent with well being, in diseases like RA, we have an increase of this process, resulting in bone lesions. Neutrophils are relevant cells in RA and osteoclastogenesis. Based on evidence from our research group, we propose Neutrophil Extracellular Traps (NETs) promote an increase of osteoclastogenesis and bone loss during an experimental arthritis. Firstly, we demonstrated that absence of NETs, through pharmacological treatment or genetic intervention, decreases bone loss and periarticular osteoclasts in joint of arthritic mice. In vitro, isolated NETs increase osteoclastogenesis, as well as resorption's function of osteoclasts. Furthermore, NETs increase the release of RANKL from osteoblasts, indicating that NETs could increase osteoclastogenesis both directly and indirectly. It is known that resolution of inflammation is fundamental to prevent damage to individuals. This process depends on mediators like annexin A1 (AnxA1), a protein present on cells like monocytes and neutrophils, acting with an inhibitory role on inflammation. AnxA1-/- mice have a worsening of inflammatory arthritis and treatment with exogenous AnxA1 decreases bone damage in wild type arthritic animals. Nonetheless, it is not yet known if NETs have a link with AnxA1. In order to understand the relationship between NETs and AnxA1 in bone lesions induced by increased osteoclastogenesis, we have set up a collaboration with Prof. Mauro Perretti, from Queen Mary University of London, UK, who is an expert in resolution of inflammation and AnxA1 biology, to investigate if NETs are able to reduce resolution mechanisms causing bone loss. So, we are applying for the BEPE fellowship program to spend 12 months in Prof. Mauro Perretti's laboratory to strengthen this project. (AU)