Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

Silvin, Aymeric; Uderhardt, Stefan; Piot, Cécile; Mesquita, Sandro Dá; Yang, Katharine; Geirsdóttir, Laufey; Mulder, Kevin; David, Eyal; Liu, Zhaoyuan; Bridlance, Cécile; Thion, Morgane Sonia; Zhang, Xiao Meng; Kong, Wan Ting; Deloger, Marc; Fontes, Vasco; Weiner, Assaf; Ee, Rachel; Dress, Regine J.; Hang, Jing Wen; Balachander, Akhila; Chakarov, Svetoslav; Malleret, Benoît; Dunsmore, Garett; Cexus, Olivier; Chen, Jinmiao; Garel, Sonia; Dutertre, Charles Antoine; Amit, Ido; Kipnis, Jonathan; Ginhoux, Florent

doi:10.1016/j.immuni.2022.07.004

Cited by 159 publications

(196 citation statements)

References 68 publications

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“…3 B). Interestingly, the 7 and 20-day samples contained a unique cluster, Cluster #3, of hybrid-like cells expressing some genes traditionally associated with only microglia and specific disease-associated activated microglia [ 11 , 31 ], such as Trem2 , Apoe , Fabp5 , and Spp1 , as well as genes traditionally associated only with cells of a monocytic lineage, such as Adgre1 , Cd74 , and H2-Aa (Fig. 3 C).…”

Section: Resultsmentioning

confidence: 99%

“…C Heatmaps showing the average gene expression in each cluster of genes associated with microglial and monocytic cell lineages (left), and genes associated with microglial and monocyte-derived macrophage activation (right). Disease-associated microglia (DAM) genes were identified previously [ 11 , 31 ], as were the macrophage activation markers [ 28 ]. D tSNE plot from this dataset combined with a previously published dataset of retinal macrophages before (0 days) and relatively early (2 days) during photoreceptor loss [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

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Structural and functional distinctions of co-resident microglia and monocyte-derived macrophages after retinal degeneration

Ronning

Karlen

Burns

2022

J Neuroinflammation

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Background Both resident microglia and invading peripheral immune cells can respond to injury and degeneration in the central nervous system. However, after dead and dying neurons have been cleared and homeostasis is re-established, it is unknown whether resident immune cells fully resume normal functions and to what degree the peripheral immune cells take up residence. Methods Using flow cytometry, in vivo retinal imaging, immunohistochemistry, and single-cell mRNA sequencing, we assess resident microglia and monocyte-derived macrophages in the retina during and after the loss of photoreceptors in the Arr1−/− mouse model of inducible degeneration. Results We find that photoreceptor loss results in a small, sustained increase in mononuclear phagocytes and, after degeneration wanes, these cells re-establish a spatial mosaic reminiscent of healthy retinas. Transcriptomic analysis revealed the population remained unusually heterogeneous, with several subpopulations expressing gene patterns consistent with mildly activated phenotypes. Roughly a third of “new resident” cells expressed markers traditionally associated with both microglial and monocytic lineages, making their etiology ambiguous. Using an inducible Cre-based fluorescent lineage tracing paradigm to confirm the origins of new resident immune cells, we found approximately equal numbers of microglia and monocyte-derived macrophages after degeneration had subsided. In vivo retinal imaging and immunohistochemical analysis showed that both subpopulations remained functionally responsive to sites of local damage, though on average the monocyte-derived cells had less morphological complexity, expressed higher levels of MHCII, and had less migratory activity than the native resident population. Conclusions Monocytic cells that infiltrate the retina during degeneration differentiate into monocyte-derived macrophages that can remain in the retina long-term. These monocyte-derived macrophages adopt ramified morphologies and microglia-like gene expression. However, they remain distinguishable in morphology and gene expression from resident microglia and appear to differ functionally, showing less responsiveness to subsequent retinal injuries. These findings support the idea that persistent changes in the local immune population that occur in response to cell loss in aging and progressive retinal diseases may include the establishment of subpopulations of bone marrow-derived cells whose ability to respond to subsequent insults wanes over time.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Structural and functional distinctions of co-resident microglia and monocyte-derived macrophages after retinal degeneration

Ronning

Karlen

Burns

2022

J Neuroinflammation

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“…Therefore, a package that uses k-means clustering, called RaceID, introduced an outlier detection method to counteract this issue 43 . Community-based detection algorithms like Louvain's algorithm, detects clusters based on 'communities', which is the basis for the popular scRNAseq tool, Seurat 44 used by many microglial researchers 6,7,16,25,34,[39][40][41][45][46][47] . Either clustering algorithm separates cells based on similarities and the proximity of each cell within the graphical projection indicates their relatedness.…”

Section: Box 1 | Microglia Heterogeneity Definitionsmentioning

confidence: 99%

Towards a definition of microglia heterogeneity

2022

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High dimensional single-cell analysis such as single cell and single nucleus RNA sequencing (sc/snRNAseq) are currently being widely applied to explore microglia diversity. The use of sc/snRNAseq provides a powerful and unbiased approach to deconvolve heterogeneous cellular populations. However, sc/snRNAseq and analyses pipelines are designed to find heterogeneity. Indeed, cellular heterogeneity is often the most frequently reported finding. In this Perspective, we consider the ubiquitous concept of heterogeneity focusing on its application to microglia research and its influence on the field of neuroimmunology. We suggest that a clear understanding of the semantic and biological implications of microglia heterogeneity is essential for mitigating confusion among researchers.

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“…The detection of a greater number of differentially expressed genes in aging microglia during OxPC injury compared to aging microglia at steady state suggest that the impact of aging becomes more pronounced during disease, highlighting a need to target microglia and restore their neuroprotective functions during MS pathology and progression in aging individuals. However, as monocyte-derived macrophages also increase during aging and neurodegeneration [8], future studies should compare their behaviour versus that of microglia in aging and in various diseases including MS, such as in their responses to to OxPCs. Evaluating their functional dif-ferences will inform on whether there is a need to specifically target each population to reduce pathology or to promote repair.…”

Section: Agingmentioning

confidence: 99%

Untitled

2022

Aging

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Aging associates with the onset and progression of neurodegenerative diseases in the central nervous system (CNS), including multiple sclerosis (MS). Notably, individuals with relapse-remitting MS convert to non-remitting secondary progressive MS with higher frequency as they age. Existing therapeutics often fail to prevent long-term neurodegeneration and disability in MS, partially because the mechanisms that drive neural injury are not fully understood. Thus, to develop better therapeutics for progressive MS, it is important to determine what mediates neurodegeneration and how risk factors such as aging accelerate deterioration. Recent single cell RNA sequencing (scRNAseq) studies report prevalent age-associated transcriptomic changes in CNS cells including astrocytes, oligodendrocytes, and microglia [1,2]. Further investigations on how aging impacts the biology of CNS cells and their ability to respond to mediators of neurodegeneration will help to identify new therapeutic strategies.

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Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

Cited by 159 publications

References 68 publications

Structural and functional distinctions of co-resident microglia and monocyte-derived macrophages after retinal degeneration

Structural and functional distinctions of co-resident microglia and monocyte-derived macrophages after retinal degeneration

Towards a definition of microglia heterogeneity

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