The Question
The nervous system and the immune system have historically been studied in siloes. Crosstalk between the two systems — and the role this intersection plays in health and disease — has long been understudied. However, the interplay between the nervous system and the immune system is critical. For example, increasing evidence indicates that inflammation is associated with neurodegeneration in aging, and that a person’s brain function and mental state can affect immunity. Disorders such as Alzheimer’s disease (AD), multiple sclerosis (MS), long COVID and some forms of cancer are thought to result from a combination of damage to the nervous system and resulting inflammation. Yet the cells, molecules and mechanisms that guide these connections are mostly unknown. To better prevent and treat diseases, we need to better understand at all levels how they develop and progress.
The Approach
Through its Neuroimmunology Initiative within the NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk scientists are working to develop a deep understanding of the crosstalk between the immune and nervous systems and the role it plays in health and disease. The Neuroimmunology Initiative encompasses three interconnected research programs:
Body to Brain: Impact of peripheral inflammation on brain cell function
In this line of research, the team will determine how different types of inflammatory events originating in the periphery — such as viral infection, aging and cancer — impact different brain cell types and regions. Additionally, they will investigate the extent to which immune cells, such as T cells, infiltrate the brain and the spinal cord following infections caused by various pathogens. This research program will provide, for the first time, (1) a spatial map of how the nervous system reacts to particular types of inflammation and cytokines, (2) the brain regions in which immune cells infiltrate and establish long-term residency after infection, and (3) the extent to which recurrent infections induce long-lasting changes in the brain’s cellular composition and foster “inflammatory memory” through the induction of epigenetic alterations in neurons and glial cells.
Within the Brain: Impact of immune signaling on brain resident cells
This line of investigation will unravel how resident brain cells, namely microglia, astrocytes and neurons, interact and influence each other during inflammatory events. The researchers will assess how this cellular crosstalk impacts brain inflammation, function and cognitive performance. They will also investigate how the immune cells that infiltrate the nervous system in response to peripheral infection interact with and impact resident brain cells and alter the inflammatory milieu and cerebrospinal fluid in the brain. Finally, they will selectively deplete specific immune cell subsets, such as memory T cells, to delineate their contribution to sustaining brain inflammation over time. Through this multifaceted approach, the team aims to provide insights into the intricate dynamics between infection, immune response and brain homeostasis. Moreover, it may unveil therapeutic targets to mitigate chronic brain inflammation, which is associated with aging and neurodegenerative diseases such as AD.
Brain to Body: Impact of neural signaling on peripheral immunity
This research will look at the flip side of the coin: how the nervous system (brain and spinal cord) senses and influences inflammation and immune responses elsewhere in the body. The scientists will first use neural tracing techniques to identify specific cell types in the brain and spinal cord that respond to inflammatory events such as infection or cancer, illuminating the neurons that relay the health status of an organ or tissue to the nervous system. They will then use genetic and pharmacological manipulations to investigate the roles of those neurons in modulating the immune responses. By activating different stress pathways (e.g., such as those regulating depression and chronic stress) in the brain and spinal cord they hope to determine whether an individual’s mental state impacts immune responses. The researchers will construct a road map of neuronal circuits and interoceptive signals that distinguish between different types of immune responses occurring in different organs. In addition, they seek to deduce how different types of neuronal stress responses impact the initiation and resolution of immune responses in the periphery.
The Neuroimmunology Initiative gives scientists the freedom to tackle currently unaddressed scientific questions, which will open fundamentally new areas of scientific inquiry across human health and disease. Ultimately, this work paves the way toward innovative therapeutic interventions for a wide range of disorders that have both a neurological and immunological component.
The project is being led by Susan Kaech and Nicola Allen at the Salk Institute’s NOMIS Center for Immunobiology and Microbial Pathogenesis in La Jolla, US.
Feature image: Astrocytes (Photo: Salk Institute)
