Local self-renewing of microglia after genetic ablation is dependent on Interleukin-1 signaling
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Abstract
The development of new fate mapping techniques helped to elucidate the ontogeny of microglia during embryonic development. Microglia precursors arise during the primitive hematopoiesis at E7.5 and develop into early progenitors found in the yolk sac at E9.5. From there they migrate through the circulation to the CNS parenchyma between E10.5-E13.5, where they persist throughout adulthood. However, the mechanisms by which these unique cells are maintained in the adult CNS still remain elusive.
In this study, we describe the Cx3Cr1CreER:iDTR system, a genetic model that allows for specific, conditional ablation of microglia in adult mice. With the help of this new genetic model we were able to deplete microglia with at least 90% efficiency. Surprisingly, the depletion was followed by rapid repopulation of the microglia compartment. The repopulation relied on CNS-resident cells, independent of bone-marrow-derived precursors, whereas the existence of a certain pre-determined microglia progenitor within the CNS is not yet completely proven. During the repopulation process, microglia formed clusters of highly proliferative cells that migrated away until normal microglia numbers were reestablished and steady state distribution was achieved. The trigger for the rapid repopulation is not yet clear, but could be driven by local progenitors in response to IL-1R signaling, since proliferating microglia expressed high levels of the interleukin-1 receptor (IL-1R), and treatment with an IL-1R antagonist during the repopulation phase impaired microglia proliferation. Furthermore, according to other tissue resident macrophages, microglia also demonstrate their potential for efficient self-renewal without the contribution of peripheral myeloid cells.