Influence of neuro-immune-metabolic interactions on invariant natural killer T lymphocytes during acute liver injury

• Grant number: 25/17120-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2026
• End date: December 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alexandre de Castro Keller
• Grantee: Carlos Hiroji Hiroki
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 24/05664-9 - The plasticity of non-conventional lymphocytes in immunological responses: perspectives and alternatives, AP.TEM

Abstract

The liver has a relevant role on the physiological metabolism as well as in the process of systemic detoxification, and due to its physioanatomy, it is a constant target of distinct insults, potentially pathological, whose consequences rely on the interactions between hepatocytes and the different resident immune cells. In this context, invariant natural killer T cells (iNKT) have stood out as they are the largest lymphoid population in the liver, but also due to their ability to modulate the biological activity of other immune and non-immune cells. During hepatic lesion, these cells can acquire distinct patterns of activation, either exacerbating either inhibiting the inflammatory response. The mechanisms that coordinate the activity of the hepatic immune cells are not completely understood; nevertheless, recent studies have demonstrated a network of nervous fibers that play roles such as afferent (communication with the central nervous system) and efferent (release of mediators), which result on the modulation of the immune response. The sensory innervation detects physiological alterations, sending inputs to the central nervous system, resulting, for example, on the activation of the sympathetic innervation of the liver, which releases neurotransmitters that act on the hepatic cells. Furthermore, the hepatic damage itself can lead to the activation of the nervous network and, as consequence, release of mediators, such as neuropeptides and neurotransmitters, of which influence directly on the function of immune cells. In this context, these mediators can alter the metabolic profile of these cells and, as consequence, the cytokine profile produced. Therefore, in the present project, we propose to characterize the spatial distribution of the hepatic innervations (sensory and sympathetic) and the different immune populations and utilize pharmacological approaches to demonstrate the relevance of the liver-brain-liver axis in models of acute hepatic lesion induced by iNKT activation. Next, we will evaluate the effector profile of the iNKT, and the possible influence of the neuropeptides or neurotransmitters derived from the hepatic innervation, as well as alterations on the metabolic profile of these cells. We believe that this work will contribute to the understanding of the neuroimmunometabolic interactions of the iNKT cells from the liver and the impact on the inflammatory processes during acute hepatic lesion. (AU)