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SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment.
- Source :
-
EMBO reports [EMBO Rep] 2024 May; Vol. 25 (5), pp. 2278-2305. Date of Electronic Publication: 2024 Mar 18. - Publication Year :
- 2024
-
Abstract
- SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Humans
Mice
Brain metabolism
Brain pathology
Cell Line, Tumor
Disease Models, Animal
Glioblastoma metabolism
Glioblastoma pathology
Glioblastoma genetics
Macrophages metabolism
Brain Neoplasms metabolism
Brain Neoplasms pathology
Brain Neoplasms genetics
Glioma metabolism
Glioma pathology
Glioma genetics
Membrane Transport Proteins metabolism
Membrane Transport Proteins genetics
Microglia metabolism
Microglia pathology
Tumor Microenvironment
Tumor Necrosis Factor-alpha metabolism
LDL-Receptor Related Proteins genetics
LDL-Receptor Related Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1469-3178
- Volume :
- 25
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- EMBO reports
- Publication Type :
- Academic Journal
- Accession number :
- 38499808
- Full Text :
- https://doi.org/10.1038/s44319-024-00117-6