Dataset Information

CD11c-expressing microglia are transient, driven by interactions with apoptotic cells

ABSTRACT: Microglia, the parenchymal macrophage of the central nervous system serve crucial remodeling functions throughout development in response to developmental cues. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer distinct roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia that express CD11c (Integrin αX, complement receptor 4, Itgax). which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia by examining the developmental contexts and dynamics for the emergence of CD11c+ microglia. We find that microglial CD11c expression tracks with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is, in part, dependent upon the TAM receptor Axl. Using selective ablation, we find similar effects on apoptotic cell clearance with depletion of CD11c+ versus non-CD11c microglia, suggesting that CD11c+ microglia are not uniquely critical for phagocytic clearance. Together, our data suggests CD11c+ microglia are a transient state induced in response to developmental apoptosis rather than a specialized subset mediating phagocytic elimination.

ORGANISM(S): Mus musculus

PROVIDER: GSE269549 | GEO | 2024/07/17

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.

Dataset Information

CD11c-expressing microglia are transient, driven by interactions with apoptotic cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets