A MAC2-positive progenitor-like microglial population is resistant to CSF1R inhibition in adult mouse brain.

Lihong Zhan,Li Gan,Li Fan,Gergey Alzaem Mousa,Yaqiao Li,Peter Dongmin Sohn,Man Ying Wong,Lay Kodama,Yungui Zhou

doi:10.7554/elife.51796

Abstract

Microglia are the resident myeloid cells in the central nervous system (CNS). The majority of microglia rely on CSF1R signaling for survival. However, a small subset of microglia in mouse brains can survive without CSF1R signaling and reestablish the microglial homeostatic population after CSF1R signaling returns. Using single-cell transcriptomic analysis, we characterized the heterogeneous microglial populations under CSF1R inhibition, including microglia with reduced homeostatic markers and elevated markers of inflammatory chemokines and proliferation. Importantly, MAC2/Lgals3 was upregulated under CSF1R inhibition, and shared striking similarities with microglial progenitors in the yolk sac and immature microglia in early embryos. Lineage-tracing studies revealed that these MAC2+ cells were of microglial origin. MAC2+ microglia were also present in non-treated adult mouse brains and exhibited immature transcriptomic signatures indistinguishable from those that survived CSF1R inhibition, supporting the notion that MAC2+ progenitor-like cells are present among adult microglia.

Highlights

Microglia are the primary innate immune cells in the central nervous system (CNS), capable of mounting inflammatory responses and phagocytosis
Similar to our previous results (Zhan et al, 2019), oral dosing of 1200 mg/kg PLX in C57BL/6J mice for two weeks resulted in about 90% removal of CD11b+ myeloid cells in the CNS (Figure 1—figure supplement 1)
Since MAC2 was shown to be a ligand for Trem2 signaling (Boza-Serrano et al, 2019), a pathway required for microglial homeostatic maintenance (Butovsky et al, 2014; Zoller et al, 2018), we focused on further investigating the Mac2+ subpopulation

Summary

Introduction

Microglia are the primary innate immune cells in the CNS, capable of mounting inflammatory responses and phagocytosis. Unlike other CNS glial cells, microglia originate from the embryonic mesoderm and follow a convoluted developmental journey (Rezaie and Male, 2002) It starts with the emergence of c-kit+ erythromyeloid progenitors in the yolk sac, known as primitive hematopoiesis, which influx into the developing parenchyma via circulation (Ginhoux et al, 2010) in an IRF-8, PU.1-dependent manner (Kierdorf et al, 2013). Complete microglial ablation has never been reported (Acharya et al, 2016; Rice et al, 2017; Huang et al, 2018; Zhan et al, 2019) These studies suggest that the adult microglial pool includes a population that does not require CSF1R signaling for survival. Our data uncovered a progenitor-like microglial state that likely contributes to the basal proliferation of microglia in the brain

Results

Discussion

Materials and methods