Skip to Content
Merck
  • SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment.

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

EMBO reports (2024-03-19)
Paulina Kaminska, Peter L Ovesen, Mateusz Jakiel, Tomasz Obrebski, Vanessa Schmidt, Michal Draminski, Aleksandra G Bilska, Magdalena Bieniek, Jasper Anink, Bohdan Paterczyk, Anne Mette Gissel Jensen, Sylwia Piatek, Olav M Andersen, Eleonora Aronica, Thomas E Willnow, Bozena Kaminska, Michal J Dabrowski, Anna R Malik
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
Sigma-Aldrich
Anti-LAMP-1 (CD107a) Antibody, clone 1D4B, clone 1D4B, from rat
Sigma-Aldrich
Anti-Glyceraldehyde-3-Phosphate Dehydrogenase Antibody, clone 6C5, clone 6C5, Chemicon®, from mouse