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SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment

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Item Type:Article
Title:SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment
Creators Name:Kaminska, P. and Ovesen, P.L. and Jakiel, M. and Obrebski, T. and Schmidt, V. and Draminski, M. and Bilska, A.G. and Bieniek, M. and Anink, J. and Paterczyk, B. and Jensen, A.M.G. and Piatek, S. and Andersen, O.M. and Aronica, E. and Willnow, T.E. and Kaminska, B. and Dabrowski, M.J. and Malik, A.R.
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.
Keywords:VPS10P Domain Receptors, Glioblastoma, Intracellular Sorting, Phenotypic Polarization, Brain Tumors, Animals, Mice
Source:EMBO Reports
ISSN:1469-221X
Publisher:Oxford University Press
Volume:25
Number:5
Page Range:2278-2305
Date:May 2024
Official Publication:https://doi.org/10.1038/s44319-024-00117-6
PubMed:View item in PubMed

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