Central nervous system regeneration is driven by microglia necroptosis and repopulation

Lloyd, Adam; Davies, Charlotte Aull; Holloway, R.; Labrak, Yasmine; Ireland, Graeme; Carradori, Dario; Dillenburg, Alessandra; Borger, Eva; Soong, Daniel; Richardson, Jill C.; Kuhlmann, Tanja; Williams, Anna; Pollard, Jeffrey W.; Rieux, Anne des; Priller, Josef; Miron, Véronique E.

doi:10.1038/s41593-019-0418-z

Cited by 236 publications

(222 citation statements)

References 20 publications

(21 reference statements)

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“…In both treated and untreated patients, we found that many macrophages expressed an intermediate activation status. Since efficient remyelination necessitates repopulation of pro‐inflammatory microglia by pro‐regenerative microglia, this finding supports that the activation status of microglia/macrophages is dynamic in vivo and occurs as a continuum, with the classically activated pro‐inflammatory and alternatively activated anti‐inflammatory phenotypes on either end of this spectrum . We finally found that the presence of these intermediately activated cells overexpressing markers of alternative activation was associated with evidence of remyelination in HSCT‐treated patients’ white matter.…”

Section: Discussionsupporting

confidence: 76%

Metachromatic leukodystrophy and transplantation: remyelination, no cross‐correction

Wolf

Breur

Plug

et al. 2020

Ann Clin Transl Neurol

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Objective In metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients. Methods Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) metachromatic leukodystrophy patients, and two age‐matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t‐test, linear regression or the nonparametric Mann–Whitney U‐test was performed to evaluate differences between the transplanted, nontransplanted, and control group. Results In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti‐inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in metachromatic leukodystrophy, we detected no enzymatic cross‐correction to resident astrocytes and oligodendrocytes. Interpretation In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross‐correction of oligo‐ and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.

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Section: Discussionsupporting

confidence: 76%

Metachromatic leukodystrophy and transplantation: remyelination, no cross‐correction

Wolf

Breur

Plug

et al. 2020

Ann Clin Transl Neurol

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“…The data indicate that TREM2 deficiency had no impact on the initial demyelination, but affected subsequent remyelination when the cuprizone treatment was prolonged, most likely by impairing myelin removal as well as myelin regeneration, which further supports a protective role for CD11c+ microglia in this paradigm (144,147). Additionally, it was reported that microglial necroptosis in circumstances of lysophosphatidylcholine demyelination leads to repopulation by pro-regenerative CD11c+ microglia, as blocking of this mechanism prevented remyelination (148). Of note, demyelination induced by mouse hepatitis virus also led to enrichment of CD11c+ microglial gene signature in the spinal cord (149).…”

Section: Multiple Sclerosismentioning

confidence: 74%

“…Of note, induction of this phenotype was not observed upon microglia exposure to Escherichia coli, zymosan particles (75), or microparticles (Marczynska et al, unpublished), suggesting that induction of CD11c+ microglia is a tightly controlled reaction to local cell damage or apoptosis, rather than to phagocytosis itself. Interestingly, microglial necroptosis in demyelination models leads to brain repopulation with CD11c+ microglia from nestin+ resident microglia (148). Similarly, nestin+ microglia colonizing the brain after microglia ablation expressed surface CD11c (98).…”

Section: Cell Deathmentioning

confidence: 99%

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

2020

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Microglial heterogeneity has been the topic of much discussion in the scientific community. Elucidation of their plasticity and adaptability to disease states triggered early efforts to characterize microglial subsets. Over time, their phenotypes, and later on their homeostatic signature, were revealed, through the use of increasingly advanced transcriptomic techniques. Recently, an increasing number of these "microglial signatures" have been reported in various homeostatic and disease contexts. Remarkably, many of these states show similar overlapping microglial gene expression patterns, both in homeostasis and in disease or injury. In this review, we integrate information from these studies, and we propose a unique subset, for which we introduce a core signature, based on our own research and reports from the literature. We describe that this subset is found in development and in normal aging as well as in diverse diseases. We discuss the functions of this subset as well as how it is induced.

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“…Detailed analysis of the Csf1r mutant phenotypes could therefore contribute to the identification of specific and universal features of organism-wide macrophage development. In addition, it is important to understand the systemic effects of CSF1R inhibition on macrophages, as inhibition of CSF1R is a clinical strategy for the intentional depletion of macrophages in various disease contexts, including Alzheimer’s disease, brain injury and cancer (Edwards et al, 2019; Lloyd et al, 2019; Tap et al, 2015; Webb et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes

Kuil

Oosterhof

Ferrero

et al. 2020

Preprint

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20Macrophages derive from multiple sources of hematopoietic progenitors. Most macrophages 21 require colony-stimulating factor 1 receptor (CSF1R), but some macrophages persist in the 22 absence of CSF1R. Here, we analyzed mpeg1:GFP-expressing macrophages in csf1r-23 deficient zebrafish and report that embryonic macrophages emerge followed by their 24 developmental arrest. In larvae, mpeg1+ cell numbers then increased showing two distinct 25 types in the skin: branched, putative Langerhans cells, and amoeboid cells. In contrast, 26 although numbers also increased in csf1r-mutants, exclusively amoeboid mpeg1+ cells were 27 present, which we showed by genetic lineage tracing to have a non-hematopoietic origin. 28They expressed macrophage-associated genes, but also showed decreased phagocytic 29 gene expression and increased epithelial-associated gene expression, characteristic of 30 metaphocytes, recently discovered ectoderm-derived cells. We further demonstrated that 31 juvenile csf1r-deficient zebrafish exhibit systemic macrophage depletion. Thus, Csf1r 32 deficiency disrupts embryonic to adult macrophage development. Csf1r-deficient zebrafish 33 are viable and permit analyzing the consequences of macrophage loss throughout life. 34 35 36 106 fate mapping and gene expression profiling, we identified csf1r DM mpeg1+ cells as 107 metaphocytes, a population of ectoderm-derived macrophage-like cells recently reported in 108 zebrafish (Alemany et al., 2018a; Lin et al., 2019). Extending our analyses, we further 109 demonstrated that adult csf1r DM fish exhibit a global defect in macrophage generation. In 110 5 conclusion, our study highlights distinct requirements for Csf1r during macrophage 111 generation and metaphocyte ontogeny, resolving part of the presumed macrophage 112 heterogeneity and their sensitivity to loss of Csf1r. 113 Results 114Zebrafish embryonic macrophages are formed independently of csf1r but display 115 migration and proliferation defects 207 both csf1r DM primitive macrophages and early microglia. 208Next, we assessed the presence of macrophages in developing csf1r DM animals by in 209 vivo fluorescence imaging of one lateral side of entire, individual larvae on 4 consecutive 210 days, starting at 5 dpf. We visualized ~450 macrophages in control animals, whereas csf1r DM 211 animals contained > 4-fold fewer (~100) ( Figure 3D). Over the next 4 days, macrophage 212 numbers in both groups remained stable ( Figure 3D). This suggests that, at this stage, there 213 is neither proliferative expansion of embryonic macrophages nor supply of macrophages 214 from an alternative source, causing macrophage numbers in csf1r DM larvae to remain much 215 lower than those in controls up to 9 dpf. Together these data indicate that, onwards from the 216 initiation of embryonic tissue colonization, proliferative expansion of macrophages remains 217 halted in csf1r DM animals.218 219 csf1r DM skin lacks highly branched putative Langerhans cells 220 8Given that macrophages are produced by consecutive waves of primiti...

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Central nervous system regeneration is driven by microglia necroptosis and repopulation

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Cited by 236 publications

References 20 publications

Metachromatic leukodystrophy and transplantation: remyelination, no cross‐correction

Metachromatic leukodystrophy and transplantation: remyelination, no cross‐correction

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes

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