Characterization of trained innate memory and immune tolerance of neural stem cells to repeated challenges in vitro.

• Grant number: 22/06375-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2022
• End date: April 30, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Alline Cristina de Campos
• Grantee: Juliana Bueno Freire
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Cells of the innate immune system can acquire "memory" via epigenetic reprogramming after stimuli with microbial ligands. This functional readjustment allows inflammatory responses to be enhanced in secondary challenges, a process called "trained innate immunity". On the other hand, these cells could also develop immunological tolerance depending on the concentration of the ligand and the pattern recognition receptors involved. In the Central Nervous System (CNS), innate immune cells such as microglia are responsible for maintaining neural function and the traffic of other cells during an insult and it has been shown that these cells are capable of developing immune training and tolerance. In 2017, Naik and colleagues demonstrated that skin stem cells respond to a second tissue insult without recruiting macrophages or T cells residing in the skin. This suggests the induction of trained innate immunity in cells not belonging to the immune system. Studies showing that microglial depletion is not necessarily lethal in mice raise the hypothesis that other types of neural cells could participate not only in active immune defense in the CNS, but could also participate in processes of trained immunity and immune tolerance. In the adult CNS, neural stem cells are restricted to two areas of the brain, called the neurogenic niche: the subventricular zone of the walls of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. The latter has received much attention because of the hippocampus' relevance to psychiatric and neurological disorders such as Major Depressive Disorder and Alzheimer's Disease. Therefore, the present proposal aimed to characterize whether embryonic and adult neural stem cells and microglia can develop trained innate immunity and immunological tolerance after successive immunological challenges in vitro. Using HIB5, SCR022 and HAPI cell lines, we will evaluate how neural stem cells present in the adult hippocampal neurogenic niche, whether embryonic respond to subsequent stimuli of the same nature or not, and the impact of these stimuli on epigenetic modulation and genes related to immune response. We will also carry out experiments to understand if and how the neural stem cells can modify the microglia response. This mechanism can help us to clarify the chronic immune modulation present in some psychiatric and neurological disorders that impact the function of the hippocampus.