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

• Final Report Year: 2021

Final Report Abstract

Microglia are brain macrophages that emerge early during embryogenesis. 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. Using genetic methods, we could show that the precursors of these cells are within the CNS: we showed that if we ablate microglia, the cells that come instead of them and populate the CNS originate from the CNS and not the bone marrow. Importantly, we found that the cytokine interleukin-1 (IL-1), plays an important role in this process. Using similar techniques, we could further show that expression of the receptor for IL-1, termed IL-1R1 by microglia cells is not critical for their function during autoimmune brain inflammation, when using a mouse model of multiple sclerosis. In another set of experiments, we could show that the one cell type where IL-1 signaling does play a role and is critical for the development of CNS autoimmunity, are the endothelial cells of the blood brain barrier. Our data show that although IL-1 signaling is important for the expansion of microglia in the CNS, it is not critical for their function during autoimmunity of the CNS but rather it is important for the integrity of the blood brain barrier.

Publications

• (2018) Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity. J Mol Med (Berl). 96(12):1279-1292
  Waisman A, Johann L
  (See online at https://doi.org/10.1007/s00109-018-1709-7)
• (2019) Novel Microglia Depletion Systems: A Genetic Approach Utilizing Conditional Diphtheria Toxin Receptor Expression and a Pharmacological Model Based on the Blocking of Macrophage Colony-Stimulating Factor 1 Receptor. Methods Mol Biol. 2034:217-230
  Kitic M, See P, Bruttger J, Ginhoux F, Waisman A.
  (See online at https://doi.org/10.1007/978-1-4939-9658-2_16)
• (2019) Unraveling the T-B tangle in anti-CD20 multiple sclerosis therapy. Proc Natl Acad Sci USA. 116(51):25376-25377
  Waisman A, Ebering A.
  (See online at https://doi.org/10.1073/pnas.1919044116)
• (2020) Microglial A20 Protects the Brain from CD8 T-Cell-Mediated Immunopathology. Cell Rep. 30(5):1585-1597
  Mohebiany AN, Ramphal NS, Karram K, Di Liberto G, Novkovic T, Klein M, Marini F, Kreutzfeldt M, Härtner F, Lacher SM, Bopp T, Mittmann T, Merkler D, Waisman A
  (See online at https://doi.org/10.1016/j.celrep.2019.12.097)