Enhancing innate immunity by interfering with the inflammatory reflex

• Grant number: 23/03454-4
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: October 01, 2023
• End date: September 18, 2024
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Luiz Guilherme de Siqueira Branco
• Grantee: Patrícia Passaglia
• Supervisor: Davide Martelli
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Università di Bologna, Italy
• Associated to the scholarship: 20/12777-3 - "Interaction between Angiotensin-converting enzyme 2 and serotonin during systemic inflammation", BP.PD

Abstract

The inflammatory reflex (IR) is a classic neural reflex composed of an afferent arm that perceives the immune challenge and transmits the information from the immune system to the central nervous system. Here specific areas elaborate this information and, in turn, activate an efferent arm that inhibits the production of pro-inflammatory cytokines and enhances that of anti-inflammatory mediators. Compared with efferent pathways, much less is known about the afferent arm of the reflex. A recent study supports prostaglandin E2 and the vagus nerve as the afferent arm of the IR. However, despite being explored, new efferent mechanisms are being pointed out and should be investigated for the subsequent promotion of therapies to control systemic inflammation in different pathophysiological contexts. In this sense, the literature points to the participation of neuropeptide Y (NPY) released after the sympathetic pathway of the inflammatory reflex to attenuate inflammatory mediators during endotoxemia. Thus, the project's main objective is to determine the nature of the afferent arm of the IR and to analyze the involved efferent mechanisms of the NPYR pathway during systemic infection. Sprague Dawley male rats (60-80 days, 300-400 g) and transgenic mice: ²2-ARs knock out (²2-KO), NPY1Rs-KO, ²2-KO + NPY1Rs-KO and C57BL6 (WT, 6-8 weeks, 20-25g) will be used for experimentation. The endotoxemic model will be induced by i.v. injection of lipopolysaccharide (60µg/kg). Indomethacin (5 and 10mg/kg) will be used in protocols to analyze the afferent pathway of IR. Surgery of greater splanchnic nerves bilaterally cut and cervical vagus cut will be realized to analyze the participation of the cholinergic and sympathetic arms in the production of inflammatory mediators. Mean values ± SD will be calculated, and statistical comparisons will be with 1-way ANOVA followed by Newman-Keuls test. P<0.05 will be considered significant. (AU)