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

Brain pathologies are thought to be associated with discrete activation modules of the resident brain macrophage population, the microglia. Circuits that restore the microglia ground state after activation, although arguably of equal importance, are even less well understood.

We recently established that sensing of the cytokine IL-10 by microglia is essential for these cells to regain critical quiescence, in absence of which animals succumb to a peripheral endotoxin challenge due to uncontrolled fatal TNF secretion (Shemer et al., Immunity 2020, PMID: 33049219). Surprisingly, we discovered that in contrast to most other tissue macrophages, microglia do not produce IL-10 themselves, but rather rely on cell infiltrates, incl. NK cells and neutrophils.
We hypothesize that microglial outsourcing of IL-10 production is an important aspect of brain physiology, as it allows for a robust, though transient microglia response.

In our project, we aim to identify the molecular mechanism(s) that repress the ability of microglia to express IL-10. Specifically, we will investigate the epigenetic state of the microglial IL-10 loci including open chromatin regions, histone modification, and specific transcription factor (TF) binding sites. We will compare acutely isolated microglia to ex vivo-cultured microglia, which gain the ability to express IL-10, and analyze TF expression changes by transcriptome profiling. Finally, we will use a CRISP/Cas9 approach to delete specific predicted TF binding sites in the IL-10 locus in the attempt to define the repressor circuit and its additional targets, and create mice harboring microglia that express IL-10 upon activation.
The latter animals will allow us to investigate the role of microglial IL-10 repression and outsourcing for neuronal fitness and higher brain functions.