Microglia Heterogeneity in the Single-Cell Era

Masuda, Takahiro; Sankowski, Roman; Staszewski, Ori; Prinz, Marco

doi:10.1016/j.celrep.2020.01.010

Cited by 534 publications

(462 citation statements)

References 77 publications

Supporting

Mentioning

402

Contrasting

Unclassified

Order By: Relevance

“…Increasing evidence indicates that microglia are a highly heterogeneous cell population [ 30 ]. Novel technologies, including RNA-seq analysis, have revealed that microglial transcriptomic and proteomic profiles could be drastically different based on criteria such as the region, time, disease, and state [ 31 ]. Simple classification as M1 or M2 phenotype does not accurately describe the heterogeneity of microglia; however, this classification is still accepted and used, especially in the clinical treatment of stroke and neurodegenerative disease [ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

Song

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background Neuroinflammation is the major pathogenesis of cerebral ischemia. Microglia are activated and polarized to either the pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype, which act as a critical mediator of neuroinflammation. Sestrin2 has pro-survival properties against ischemic brain injury. However, whether sestrin2 has an anti-inflammatory function by shifting microglia polarization and its underlying mechanism is unknown. Methods Adult male C57BL/6 mice (N = 108) underwent transient middle cerebral artery occlusion (tMCAO) and were treated with exogenous sestrin2. Neurological deficit scores and infarct volume were determined. Cell apoptosis was examined by TUNEL staining and Western blotting. The expression of inflammatory mediators, M1/M2-specific markers, and signaling pathways were detected by reverse transcription-polymerase chain reaction, immunostaining, and Western blotting. To explore the underlying mechanism, primary neurons were subjected to oxygen-glucose deprivation (OGD) and then treated with oxygenated condition medium of BV2 cells incubated with different doses of sestrin2. Results Sestrin2 attenuated the neurological deficits, infarction volume, and cell apoptosis after tMCAO compared to those in the control (p < 0.05). Sestrin2 had an anti-inflammatory effect and could suppress M1 microglia polarization and promote M2 microglia polarization. Condition medium from BV2 cells cultured with sestrin2 reduced neuronal apoptosis after OGD in vitro. Furthermore, we demonstrated that sestrin2 drives microglia to the M2 phenotype by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway and restoring autophagic flux. Conclusions Sestrin2 exhibited neuroprotection by shifting microglia polarization from the M1 to M2 phenotype in ischemic mouse brain, which may be due to suppression of the mTOR signaling pathway and the restoration of autophagic flux.

show abstract

Section: Discussionmentioning

confidence: 99%

Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

Song

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…However, we encountered a striking sex- and CNS compartment-related bias in treatment efficacy in Ppt1 −/− mice. These observations emphasize the contextual and regional heterogeneity of microglia/macrophages [ 32 , 52 , 69 ] and furthermore highlight the need for a more detailed analysis of sex- and brain region-specific differences with regards to assessments of prospective treatment approaches.…”

Section: Introductionmentioning

confidence: 98%

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Berve

West²,

Martini

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. Methods We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1−/− mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Conclusions Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.

show abstract

“…In the adult brain, microglia are essential surveyors and phagocytes, maintaining homeostasis in the brain [ 53 , 54 , 55 , 56 , 57 ]. Only a limited number of genes and proteins are found in human and rodent glia, and therefore the direct translation of results from animal to human studies is restricted [ 58 , 59 ]. There is no discrete set of biomarkers which uniquely identify microglia under physiological and pathological conditions [ 60 , 61 ].…”

Section: Neurons and Glial Cells In The Brainmentioning

confidence: 99%

Dendrimers as Modulators of Brain Cells

2020

View full text Add to dashboard Cite

Nanostructured hyperbranched macromolecules have been extensively studied at the chemical, physical and morphological levels. The cellular structural and functional complexity of neural cells and their cross-talk have made it rather difficult to evaluate dendrimer effects in a mixed population of glial cells and neurons. Thus, we are at a relatively early stage of bench-to-bedside translation, and this is due mainly to the lack of data valuable for clinical investigations. It is only recently that techniques have become available that allow for analyses of biological processes inside the living cells, at the nanoscale, in real time. This review summarizes the essential properties of neural cells and dendrimers, and provides a cross-section of biological, pre-clinical and early clinical studies, where dendrimers were used as nanocarriers. It also highlights some examples of biological studies employing dendritic polyglycerol sulfates and their effects on glia and neurons. It is the aim of this review to encourage young scientists to advance mechanistic and technological approaches in dendrimer research so that these extremely versatile and attractive nanostructures gain even greater recognition in translational medicine.

show abstract

Microglia Heterogeneity in the Single-Cell Era

Cited by 534 publications

References 77 publications

Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Dendrimers as Modulators of Brain Cells

Contact Info

Product

Resources

About