High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease

Mrdjen, Dunja; Pavlovic, Anto; Hartmann, Felix J.; Schreiner, Bettina; Utz, Sebastian G.; Leung, Brian P.; Lelios, Iva; Heppner, Frank L.; Kipnis, Jonathan; Merkler, Doron; Greter, Melanie; Becher, Burkhard

doi:10.1016/j.immuni.2018.01.011

Cited by 726 publications

(591 citation statements)

References 73 publications

Supporting

Mentioning

553

Contrasting

Unclassified

Order By: Relevance

“…1d). This separation of disease-associated CNS immune cell populations agrees with a recent single-cell cytometry-based study [34]. Our transcriptome-based cluster analysis of all 944 microglial cells using the RaceID2 algorithm identified ten clusters (C1-C10), of which cells from C4, C8 and C9 mapped mainly to the tail (Fig.…”

Section: Resultssupporting

confidence: 90%

Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

Tay

Sagar

Dautzenberg

et al. 2018

acta neuropathol commun

View full text Add to dashboard Cite

Microglia are brain immune cells that constantly survey their environment to maintain homeostasis. Enhanced microglial reactivity and proliferation are typical hallmarks of neurodegenerative diseases. Whether specific disease-linked microglial subsets exist during the entire course of neurodegeneration, including the recovery phase, is currently unclear. Taking a single-cell RNA-sequencing approach in a susceptibility gene-free model of nerve injury, we identified a microglial subpopulation that upon acute neurodegeneration shares a conserved gene regulatory profile compared to previously reported chronic and destructive neurodegeneration transgenic mouse models. Our data also revealed rapid shifts in gene regulation that defined microglial subsets at peak and resolution of neurodegeneration. Finally, our discovery of a unique transient microglial subpopulation at the onset of recovery may provide novel targets for modulating microglia-mediated restoration of brain health.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0584-3) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultssupporting

confidence: 90%

Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

Tay

Sagar

Dautzenberg

et al. 2018

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…Next, we considered the possibility that monocytes/myeloid cells infiltrating into the CNS of PLPmut mice or compensatorily recruited myeloid cells upon PLX3397 treatment from outside the CNS contribute to the identified resident CD11b+ cells. Flow cytometry showed that the large majority of CD11b+ cells freshly isolated from the CNS of Wt and PLPmut mice were CD45low and Siglec H+ (Figure a), a microglia‐specific marker (Konishi et al, ; Mrdjen et al, ). Using the microglia‐specific antibody against the transmembrane protein 119 [Tmem119 (Bennett et al, )] on optic nerve sections, nearly all CD11b+ cells in the parenchyma were also Tmem119+ in treated and untreated Wt and PLPmut mice, further arguing against a recruitment of nonresident, myeloid cells from outside the CNS (Figure b).…”

Section: Resultsmentioning

confidence: 99%

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Groh

Klein

Berve

et al. 2018

Glia

View full text Add to dashboard Cite

Genetically caused neurological disorders of the central nervous system (CNS) usually result in poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with disease‐amplifying neuroinflammation, a feature shared by progressive forms of multiple sclerosis (PMS), another poorly treatable disorder of the CNS. We have previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients fulfilling clinical criteria for multiple sclerosis (MS). These mutations cause a loss of function of the gene product resulting in a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation comprising adaptive immune reactions promotes disease progression in these PLP1 mutant models, opening the possibility to improve disease outcome of the respective disorders by targeting/modulating inflammation. We here show that PLX3397, a potent inhibitor of the CSF‐1R and targeting innate immune cells, attenuates neuroinflammation in our models by reducing numbers of resident microglia and attenuating T‐lymphocyte recruitment in the CNS. This leads to an amelioration of demyelination, axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the inner retinal composite layer in longitudinal studies using noninvasive optical coherence tomography. Our findings identify microglia as important promoters of neuroinflammation‐related neural damage and CSF‐1R inhibition as a possible therapeutic strategy not only for PMS but also for inflammation‐related genetic diseases of the nervous system for which causal treatment options are presently lacking.

show abstract

“…Additionally, a number of papers have reported fundamental differences in the genetic profiles of cultured primary microglia compared to their freshly isolated adult counterparts [37] indicating that in vitro, microglia may not achieve a full resting state. Furthermore, it is important to note that microglia in a healthy mouse brain have very low expression of MHCII at baseline [14, 38, 39]. Therefore, it is difficult to know whether the in vitro expression at baseline is due to compensatory transcriptional pathways, intrinsic differences between in vitro and in vivo cells, or baseline biological differences in activation status between WT and CIITA knock-out.…”

Section: Discussionmentioning

confidence: 99%

Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease

Williams

Schonhoff

Jurkuvenaite

et al. 2018

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundParkinson’s disease (PD) is characterized by intracellular alpha-synuclein (α-syn) inclusions, progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and activation of the innate and adaptive immune systems. Disruption of immune signaling between the central nervous system (CNS) and periphery, such as through targeting the chemokine receptor type 2 (CCR2) or the major histocompatibility complex II (MHCII), is neuroprotective in rodent models of PD, suggesting a key role for innate and adaptive immunity in disease progression. The purpose of this study was to investigate whether genetic knockout or RNA silencing of the class II transactivator (CIITA), a transcriptional co-activator required for MHCII induction, is effective in reducing the neuroinflammation and neurodegeneration observed in an α-syn mouse model of PD.MethodsIn vitro, we utilized microglia cultures from WT or CIITA −/− mice treated with α-syn fibrils to investigate inflammatory iNOS expression and antigen processing via immunocytochemistry (ICC). In vivo, an adeno-associated virus (AAV) was used to overexpress α-syn in WT and CIITA −/− mice as a model for PD. Concurrently with AAV-mediated overexpression of α-syn, WT mice received CIITA-targeted shRNAs packaged in lentiviral constructs. Immunohistochemistry and flow cytometry were used to assess inflammation and peripheral cell infiltration at 4 weeks post transduction, and unbiased stereology was used 6 months post transduction to assess neurodegeneration.ResultsUsing ICC and DQ-ovalbumin, we show that CIITA −/− microglial cultures failed to upregulate iNOS and MHCII expression, and had decreased antigen processing in response to α-syn fibrils when compared to WT microglia. In vivo, global knock-out of CIITA as well as local knockdown using lentiviral shRNAs targeting CIITA attenuated MHCII expression, peripheral immune cell infiltration, and α-syn-induced neurodegeneration.ConclusionOur data provide evidence that CIITA is required for α-syn-induced MHCII induction and subsequent infiltration of peripheral immune cells in an α-syn mouse model of PD. Additionally, we demonstrate that CIITA in the CNS drives neuroinflammation and neurodegeneration. These data provide further support that the disruption or modulation of antigen processing and presentation via CIITA is a promising target for therapeutic development in preclinical animal models of PD.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1286-2) contains supplementary material, which is available to authorized users.

show abstract

High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease

Cited by 726 publications

References 73 publications

Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease

Contact Info

Product

Resources

About