The role of IL-1 signaling in the regulation of microglia development and function

• Applicant: Professor Dr. Ari Waisman
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317624411

Microglia are brain macrophages that emerge from early erythro-myeloid precursors in the embryonic yolk sac and migrate to the brain mesenchyme prior to the formation of the blood brain barrier. These cells seed the brain, and proliferate until they have formed a grid-like distribution in the central nervous system (CNS) that is maintained throughout lifespan. Recently, we generated a new mouse line that allows for the conditional ablation of microglia cells in adult mice. We found that the microglia compartment was reconstituted within one week after depletion, in a process that relies entirely on CNS-resident cells. By gene expression profiling, we found high expression of the interleukin-1 (IL-1) receptor in repopulating microglia. Neutralized by treatment with an IL-1 receptor (IL-1R1) antagonist during the repopulation phase impaired microglia proliferation. Furthermore, we found that conditional deletion of the IL-1R1 in microglia resulted in reduced numbers of microglia, but with an increased number of processes in the remaining microglia cells. Using the microglia ablation system we plan to investigate two questions related to these cells: First, we plan to start what are the microglia progenitor cells in the CNS. Secondly, we plan to keep mice depleted of microglia and investigate how lack of these cells affects the cognitive and behavioral phenotype of the mice. To analyze the role of IL-1 signaling on microglia development and function, we will use the mice lacking IL-1R1 in microglia. Furthermore, we will use a second mouse model developed in our lab that allows for the conditional deletion of the IL-1 receptor antagonist IL-1R2 in microglia, thus making these cells more sensitive to IL-1 signaling. Using these mouse strains, we will investigate the importance of IL-1 signaling in the development, maintenance, and function of microglia, including their role during inflammation and autoimmunity. In addition, we will test how deletion of IL-1 signaling in microglia (by deletion of IL-1R1) or enhancing this signaling (by deletion of IL-1R2) affects behavioral phenotype of the mice. IL-1alpha and IL-1beta are central players in CNS inflammation, but the impact of these cytokines on microglia during inflammation is not thoroughly investigated. To study CNS inflammation we will use two disease models, one for brain trauma where we will induce traumatic brain injury (TBI) in the mice. In the second autoimmune disease model, we will induce disease in a mouse model of multiple sclerosis termed experimental autoimmune encephalomyelitis (EAE). TBI and EAE will be induced in mice where microglia lack the expression of IL-1R1 and therefore cannot respond to IL1 signaling, or where these cells lack IL-1R2 and therefore hyper respond to such signaling. The studies presented in this proposal should help to better understand the role of microglia in vivo and the role they play in CNS inflammation and autoimmunity.

• DFG Programme: Research Grants