Grant: Project Grant

This project is at the crossroads of neuroscience and immunology. It aims at understanding the role of the cytokine interleukin (IL)-1ß, a molecule that allows immune cells to communicate with each other, in multiple sclerosis (MS). Because of the availability of transgenic mouse lines lacking key molecules of this signalling system or having fluorescently labeled neurons, glia and immune cells, we have decided to focus our work on an animal model of MS called experimental autoimmune encephalomyelitis (EAE). Up to now, these transgenic animals have allowed us to demonstrate that IL-1ß has early detrimental effects, causing loss of neurons and their projections (termed axons), myelin sheaths and neurological function. Our results show that the negative effects of IL-1ß are mediated by a subclass of innate immune cells called neutrophils and macrophages, and involve stimulation of the IL-1 receptor (IL-1R1) present at the surface of certain veins draining the central nervous system (CNS). More specifically, we showed that IL-1ß production by innate immune cells is a critical step for their mobilization inside the CNS. Furthermore, we found that the subsequent activation of IL-1R1 signaling in CNS blood vessels induces a communication loop that drives neuroinflammation and the recruitment of autoaggressive (termed effector) lymphocytes into the CNS, eventually leading to immune attacks and demyelination. In this grant proposal, we aim at identifying the exact molecules involved in the production of IL-1 by both subclasses of innate immune cells involved. Since IL-1 can influence many types of immune and CNS cells (e.g. blood vessels, neurons, T lymphocytes, etc.), we also want to better understand their interplay in the attack phase. Finally, we want to determine whether we can use anti-IL-1 therapies (many are currently approved for arthritis) or downstream molecules to prevent EAE development and/or progression and to offer an additional therapy for MS patients.