TYPE 3 INNATE LYMPHOID CELLS AT THE INTERFACE OF THE IMMUNE SYSTEM AND NERVOUS SYSTEM

• Grant number: 25/01409-7
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: October 01, 2025
• End date: September 30, 2030
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Leandro Pires Araujo
• Grantee: Leandro Pires Araujo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Alessandro dos Santos Farias ; Alexandre Alarcon Steiner ; Alexandre de Castro Keller ; Alexandre Salgado Basso ; Marco Aurélio Ramirez Vinolo ; Niels Olsen Saraiva Câmara ; Pedro Manoel Mendes de Moraes Vieira
• Associated scholarship(s): 25/26752-6 - The Impact of the Sympathetic Nervous System on the Immune Response to Citrobacter Rodentium Intestinal Infection, BP.MS

Abstract

The microbiota is a complex community of microorganisms that coexist in association with the human body. The immune system is a network of cells and molecules contribute to the body's functioning and protection. It is known that the microbiota plays a fundamental role in the host's homeostasis and immune response. Thus, the intestinal mucosa has various types of cells from both innate and adaptive immunity, which play an essential role in distinguishing commensal organisms from pathogens. Additionally, the intestine contains its own nervous system, the enteric nervous system, which participates in important communication within the gut-brain axis. Recently, the essential role of the microbiota in the gut-brain axis has been demonstrated in modulating homeostatic function and central nervous system inflammation. Within this complex context, the role of the immune response to the microbiota is a crucial factor in host protection and homeostasis (2). Type 3 innate lymphoid cells (ILC3s) and CD4+ T helper 17 cells (Th17) play an important role in responding to bacteria and in autoimmunity. In this context, the present project aims to achieve the following main objectives: 1) evaluate the role of specific bacteria and ILC3s in generating neuroinflammation, and 2) assess the effect of the sympathetic nervous system (SNS) on ILC3s during intestinal inflammation. To achieve these goals, we will use strategies involving the deletion of bacterial communities or colonization of animals with specific bacteria in germ-free mice (the facility under construction is funded by FAPESP) in the development of experimental autoimmune encephalomyelitis (EAE). Additionally, we will use mice deficient in ILC3s to evaluate neuroinflammation in the central nervous system (CNS). ILC3s express alpha-2a and alpha-1b adrenergic receptors (ADRA2 and ADRA1B) and can respond to SNS-derived stimuli. Therefore, we will pharmacologically treat ILC3 cells in vitro with agonists and antagonists of ADRA2A and ADRA1B receptors and analyze the role of these receptors in the activation and cytokine production by ILC3s. Furthermore, we will generate mice specifically lacking ADRA2A and ADRA1B in ILC3s, referred to as Adra2a¿ILC3 or Adra1b¿ILC3 mice, to assess intestinal inflammation and neuroinflammation in the absence of adrenergic signaling in ILC3s. This investigation is crucial for understanding how ILC3s and the microbiota may influence and potentiate neuroinflammation. Moreover, it is essential to comprehend how neuromodulation in ILC3s can alter intestinal inflammation and inflammatory bowel diseases. (AU)