Role of NLRs receptors in immunoregulation mechanisms of the type 1 and 2 diabetes: identification of potential therapeutic targets

• Grant number: 12/10395-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: December 01, 2012 - November 30, 2017
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Daniela Carlos Sartori
• Grantee: Daniela Carlos Sartori
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: João Santana da Silva
• Associated grant(s): 18/14815-0 - Evaluation of the intestinal microbioma profile and of the therapeutic potential of intervention strategies in the immunopathogeny of type 1 and 2 Diabetes, AP.JP2; 17/03012-0 - Mitochondrial DNA activates the NLRP3 inflammasome and predisposes to type 1 diabetes in murine model, PUB.ART
• Associated scholarship(s): 16/25116-0 - Evaluation of the expression profile and function of AIM2 inflammasome in intestinal mucosa during diabetes type 1 experimental, BP.MS; 16/10641-1 - Evaluation of the activation and role of the NLRP1 inflammasome in the immune response in type 1 diabetes, BP.DR; 14/21020-2 - Study of intestinal Th17 response role in obesity-induced type 2 diabetes, BP.MS; + associated scholarships 14/15462-2 - Evaluation of NOD2 receptor role in insulin resistance and type 2 diabetes, BP.IC; 13/22767-1 - Evaluation of NOD2 receptor role in insulin resistance and type 2 diabetes, BP.IC; 12/24267-3 - Role of NLR receptors in the immunoregulation mechanisms in the type 1 and 2 diabetes: identification of new therapeutic targets, BP.JP - associated scholarships

Abstract

Alarming rates of diabetes mellitus (DM) demonstrated that this disease has become a major problem in public health field worldwide. Currently, there are about six million of diabetic patients in Brazil. The etiology of diabetes remains unclear, but it is known that the risk of developing the disease is determined by genetic factors and the interference of environmental factors including viral infections, food, toxins, stress and intestinal microbiota. T1D is characterized by pancreas dysfunction resulting from autoimmune selective destruction of the insulin-producing ² cells of the islets of Langerhans by autoreactive T lymphocytes. In contrast, the T2D is a systemic autoinflammatory disorder associated with obesity, triggered by the activation of innate immunity cells that leads to insulin resistance. Despite these differences, the inflammatory response drived to self-constituents represents a common denominator in the development of both DM1 and DM2. More recently it was discovered that endogenous markers called damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) are recognized by receptors cytosolic NLR (NOD-like receptors) resulting in several proinflammatory cytokine production. In spite of inflammation represents a central axis in the DM development, only few experimental studies have evaluated the functional role of NLR receptors in T1D and T2D pathogenesis. Initially, we intend to evaluate the role of NLRP1 NLRP3 receptors in inflammatory response and adaptive immunity polarization mediated by lymphocytes in T1D. In parallel, we aim to investigate the importance of receptors NOD1 and NOD2 in innate immunity modulation dependent on intestinal microbiota alterations in T2D. Considering the high incidence of DM, particularly its complications, it is important to search for new knowledge about the pathogenesis of these diseases. Therefore, our aim is to evaluate the involvement of NLRs receptors and their signaling pathways during the T1D and T2D onset. It is important to mention that the identification of new molecular targets could be used in the formulation and implementation of therapeutic strategies against these diseases, but also improve the quality of life by minimizing the progression of the diabetic complications. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CARLOS, DANIELA; COSTA, FREDERICO R. C.; PEREIRA, CAMILA A.; ROCHA, FERNANDA A.; YAOCHITE, JULIANA N. U.; OLIVEIRA, GABRIELA G.; CARNEIRO, FERNANDO S.; TOSTES, RITA C.; RAMOS, SIMONE G.; ZAMBONI, DARIO S.; et al. Mitochondrial Dna activates the nlrP3 inflammasome and Predisposes to Type 1 Diabetes in Murine Model. FRONTIERS IN IMMUNOLOGY, v. 8, FEB 25 2017. (12/10395-0, 13/08216-2)

CARLOS, DANIELA; PEREZ, MALENA M.; LEITE, JEFFERSON A.; ROCHA, FERNANDA A.; MARTINS, LARISSA M. S.; PEREIRA, CAMILA A.; FRAGA-SILVA, THAIS F. C.; PUCCI, TAIS A.; RAMOS, SIMONE G.; CAMARA, NIELS O. S.; et al. NOD2 Deficiency Promotes Intestinal CD4+T Lymphocyte Imbalance, Metainflammation, and Aggravates Type 2 Diabetes in Murine Model. FRONTIERS IN IMMUNOLOGY, v. 11, JUL 7 2020. (12/10395-0, 13/08216-2)

ELIAS-OLIVEIRA, JEFFERSON; LEITE, JEFFERSON ANTONIO; PEREIRA, ITALO SOUSA; GUIMARAES, JHEFFERSON BARBOSA; MANSO, GABRIEL MARTINS DA COSTA; SILVA, JOAO SANTANA; TOSTES, RITA CASSIA; CARLOS, DANIELA. NLR and Intestinal Dysbiosis-Associated Inflammatory Illness: Drivers or Dampers?. FRONTIERS IN IMMUNOLOGY, v. 11, AUG 11 2020. (18/14815-0, 12/10395-0)

COSTA, FREDERICO R. C.; LEITE, JEFFERSON A.; RASSI, DIANE M.; DA SILVA, JOSIANE F.; ELIAS-OLIVEIRA, JEFFERSON; GUIMARAES, JHEFFERSON B.; FOSS-FREITAS, MARIA C.; CAMARA, NIELS O. S.; PONTILLO, ALESSANDRA; TOSTES, RITA C.; et al. LRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabete. CELL REPORTS, v. 35, n. 8, MAY 25 2021. (12/10395-0, 18/14815-0, 13/08216-2)

COSTA, FREDERICO R. C.; FRANCOZO, MARCELA C. S.; DE OLIVEIRA, GABRIELA G.; IGNACIO, ALINE; CASTOLDI, ANGELA; ZAMBONI, DARIO S.; RAMOS, SIMONE G.; CAMARA, NIELS O.; DE ZOETE, MARCEL R.; PALM, NOAH W.; et al. Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset. JOURNAL OF EXPERIMENTAL MEDICINE, v. 213, n. 7, p. 1223-1239, JUN 27 2016. (12/10395-0, 13/08216-2)

PEREZ, MALENA M.; MARTINS, LARISSA M. S.; DIAS, MURILO S.; PEREIRA, CAMILA A.; LEITE, JEFFERSON A.; GONCALVES, ENRICO C. S.; DE ALMEIDA, PAULA Z.; DE FREITAS, EMANUELLE N.; TOSTES, RITA C.; RAMOS, SIMONE G.; et al. Interleukin-17/interleukin-17 receptor axis elicits intestinal neutrophil migration, restrains gut dysbiosis and lipopolysaccharide translocation in high-fat diet-induced metabolic syndrome model. IMMUNOLOGY, v. 156, n. 4, p. 339-355, APR 2019. (12/10395-0, 13/08216-2, 14/21020-2)

LEITE, JEFFERSON ANTONIO; PESSENDA, GABRIELA; GUERRA-GOMES, ISABEL C.; MENDONCA DE SANTANA, ALYNNE KAREN; PEREIRA, CAMILA ANDRE; CAMPOS COSTA, FREDERICO RIBEIRO; RAMOS, SIMONE G.; ZAMBONI, DARIO SIMOES; CAETANO FARIA, ANA MARIA; DE ALMEIDA, DANILO CANDIDO; et al. The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway. CELLS, v. 9, n. 4, APR 2020. (12/10395-0, 16/25116-0, 13/08216-2)