The interplay between intestinal neuroimmune circuits and iNKT in the physiology of the gut/liver axis

• Grant number: 22/00181-4
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2022
• End date: October 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Alexandre de Castro Keller
• Grantee: Alexandre de Castro Keller
• Principal researcher abroad: Jhimmy Talbot
• Institution abroad: Fred Hutchinson Cancer Research Center (Fred Hutch), United States
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 21/11200-7 - The role of natural killer T cells on liver homeostasis, AP.R

Abstract

The gut lumen contains several microbial agents that are essential for digestion and so for nutrient supply. The local immune compartment is critical for shaping the gut microbiota and maintaining the intestinal barrier. The iNKTs influence both the microbiota profile and intestinal inflammation, whereas the IL-22-producing ILC3 cells are essential to control bacterial translocation from the gut. The leak in the gut barrier allows bacteria and their components to achieve the liver through the portal vein. Their elimination is crucial to avoid bacteria spread and, consequently, sepsis. Dr. Talbot showed that the production of IL-22 by gut-associated ILC3 cells is inhibited by the activation of vasoactive intestinal peptide-producing enteric neurons (VIPens) during food consumption, generating a circadian inhibition of ILC3. In this scenario, IL-22 reduces gut bacterial translocation and decreases fat absorption. New preliminary data from Dr. Talbot's laboratory indicate that the fat content in the diet stimulates VIPens that inhibit the production of IL-22 by ILC3. As a consequence of the decrease in IL-22 secretion, there is a reduction in the intestinal protective immune barrier and an increase in the absorption of lipids from the diet. Although the "turn-off" of the ILC3-mediated intestinal barrier in the VIPens-ILC3-IL-22 circuit is demonstrated, the "turn-on" switch of other immune mechanisms that keep the intestinal barrier intact remains unclear. We hypothesize that gut-associated iNKTs act as lipids sensors during feeding, restoring the circadian tonus of the intestinal barrier. In addition, despite the tight circadian control of the gut barrier, there is a translocation of bacteria and microbial products from the gut to the liver, where iNKTs, which are essential to the physiological control of bacteria spreading, can be activated. Although several studies showed that hepatic iNKT cells are necessary to control bacteria spreading to the liver, the knowledge about their circadian activation by feeding-fasting cycles and the implications for liver physiology is scarcer. Moreover, because IL-22-producing ILC3 exerts a protective role in liver injury, it is correct to suppose that the relationship iNKT/ILC3 is also essential to maintain liver physiology. Thus, this proposal aims to put together our expertise to study the influence of the interplay between iNKT and the VIPen-ILC3 neuroimmune circuit on the physiology of the gut/liver axis. (AU)