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

• Published in: EMBO reports 2024-05, Vol.25 (5), p.2278-2305
• Main Authors: Kaminska, Paulina, Ovesen, Peter L, Jakiel, Mateusz, Obrebski, Tomasz, Schmidt, Vanessa, Draminski, Michal, Bilska, Aleksandra G, Bieniek, Magdalena, Anink, Jasper, Paterczyk, Bohdan, Jensen, Anne Mette Gissel, Piatek, Sylwia, Andersen, Olav M, Aronica, Eleonora, Willnow, Thomas E, Kaminska, Bozena, Dabrowski, Michal J, Malik, Anna R
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Brain - metabolism; Brain - pathology; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor; Disease Models, Animal; EMBO03; EMBO20; EMBO37; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Humans; Life Sciences; Macrophages - metabolism; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Microglia - metabolism; Microglia - pathology; Tumor Microenvironment; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00117-6

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. Synopsis The sorting receptor SorLA shapes the functional properties of glioma-associated microglia/macrophages by restraining TNFα release. In a murine glioma model, loss of SorLA unlocks inflammatory responses, which is accompanied by tumor inhibition. SorLA levels are increased in glioma-supportive microglia/macrophages but decrease upon pro-inflammatory stimulation. SorLA binds TNFα and modulates its intracellular trafficking. Loss of SorLA promotes TNFα release from microglia. SorLA deficiency exacerbates inflammation in the brain microenvironment and limits tumor growth in a murine glioma model. The sorting receptor SorLA shapes the functional properties of glioma-associated microglia/macrophages by restraining TNFα release. In a murine glioma model, loss of SorLA unlocks inflammatory responses, which is accompanied by tumor inhibition.