Microglial IL-10 expression and the impact of CNS-wide microglia responses on higher brain function

• Applicant: Professor Dr. Steffen Jung
• Subject Area: Anatomy and Physiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500215759

Microglia are brain-resident macrophages and recently gained major attention as key players in central nervous system (CNS) development, maintenance and disorders. Studies in the respective animal models suggest that distinct brain pathologies, such as Alzheimer Disease and Multiple Sclerosis, could to be associated with discrete microglia activation patterns that might be targets for therapeutic intervention. Mechanisms that ensure that microglia regain quiescence following their activation remain however less well understood although of equal potential clinical importance. We recently performed a detailed mechanistic characterization of such a critical ‘microglia silencing circuit’ that relies on the anti-inflammatory cytokine IL-10. Absence of this control circuit specifically from microglia resulted in their deleterious hyper-activation and turned an otherwise harmless stimulus lethal for the respective animals. Of note, most tissue macrophages express IL-10 to curb their own activation. Interestingly though, we found that microglial IL-10 expression seems actively prohibited through a specific epigenetic mechanism. Rather, the cells rely on the delayed provision of IL-10 by other immune cells to restore quiescence. We hypothesize that this critical delay of microglial IL-10 exposure allows for a characteristic robust microglia response, involving cytokines and other key mediators that can affect neurons and other glia. The aim of this study is ultimately to understand the physiological role of this transient brain-wide response. We propose to approach this question by two complementary objectives. We first will use advanced chromatin profiling followed by targeted mutagenesis to molecularly define the epigenetic mechanism that prevents microglial IL-10 expression. This will also reveal additional gene targets of this control circuit, which represents a key feature of microglia identity. In the second part of the project, we will investigate the impact of the altered brain-wide microglia response on other brain cells, including glia and neurons, gender differences, as well as higher brain functions, including behavior.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2395: Local and peripheral drivers of microglial diversity and function
• International Connection: Israel