Genetic Cell Ablation Reveals Clusters of Local Self-Renewing Microglia in the Mammalian Central Nervous System

Abstract

During early embryogenesis, microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how the tissue-resident macrophages are maintained throughout the organism's lifespan still remains unclear. Here, we describe a system that allows specific, conditional ablation of microglia in adult mice. We found that the microglial compartment was reconstituted within 1 week of depletion. Microglia repopulation relied on CNS-resident cells, independent from bone-marrow-derived precursors. During repopulation, microglia formed clusters of highly proliferative cells that migrated apart once steady state was achieved. Proliferating microglia expressed high amounts of the interleukin-1 receptor (IL-1R), and treatment with an IL-1R antagonist during the repopulation phase impaired microglia proliferation. Hence, microglia have the potential for efficient self-renewal without the contribution of peripheral myeloid cells, and IL-1R signaling participates in this restorative proliferation process.

New tools for studying microglia in the mouse and human CNS

“…These results reflect purity and that Tmem119 IR is sufficient to isolate microglia by P14. We calculated percentile ranks for several canonical activation genes for our naïve and LPS-stimulated samples, as well as five published datasets (15,17,30,33,34); these datasets were generated using CD45 or Cx3cr1 rather than a specific microglia marker, such as Tmem119, and used enzymatic digestion or Percoll for dissociation and myelin depletion. Compared with published profiles, canonical activation marker expression (Tnf, Il1b, Nfkb2) was significantly reduced in our naïve microglia, providing evidence that our procedure limits microglial activation (SI Appendix, Fig.…”

Interleukin-1 in Stroke

“…28 We have recently generated floxed-IL-1R1 mice that lack all known IL-1 receptors, which will allow confirmation of the role of IL-1R1 in stroke and more importantly the cell type that mediates IL-1 actions. 29 In the early years of the new millennium, there were, in comparison with a decade previously, fewer investigations of IL-1 inhibition in stroke. Although one of these studies did report that delayed (3 hours) administration of IL-1Ra still provided protection after tMCAO in the rat, this was still with central (intracerebroventricular) delivery.…”

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

“…Resident Microglia in the CNS Resident microglia perform a self-renewal process in physiological and pathological conditions [12,13]. To investigate whether circulating myelomonocytic cells participate in the renewal of microglia, syngeneic parabiosis mice were used for blood connection without BM transplantation.…”

“…More specifically, monocytes are mainly divided into two groups, namely the inflammatory monocytes (Ly-6C hi CCR2 + CX3CR1 lo ) and resident monocytes (Ly-6C lo CCR2 − CX3CR1 hi ) [36], and Ly-6C hi (which are Gr-1 + CCR2 + CX3CR1 lo ) monocytes are the main source of BM-derived microglia [17,36]. In addition, BM-derived macrophages permanently populated the CNS and contributed to the microglia pool in lethally irradiated DTRMG (diphtheria toxin receptor especially on microglia) mice with BM transplantation [12]. In another study of brain ischemia, BM-derived macrophages and monocytes both invaded the brain.…”

“…These microglia progenitors invade the brain and the retina through the formation of blood circulation during fetal development and ultimately give rise to the microglia pool [11]. After birth, the renewal of the microglia pool primarily relies on the self-proliferation of embryonic invaded microglia, namely the resident microglia [12,13].…”