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Triggering MSR1 promotes JNK-mediated inflammation in IL-4-activated macrophages

Lookup NU author(s): Professor Matthias TrostORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2019 The Authors. Published under the terms of the CC BY 4.0 license Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4-activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4-activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo. Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization.

Publication metadata

Author(s): Guo M, Hartlova A, Gierlinski M, Prescott A, Castellvi J, Losa JH, Petersen SK, Wenzel UA, Dill BD, Emmerich CH, Ramon Y Cajal S, Russell DG, Trost M

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2019

Volume: 38

Issue: 9

Online publication date: 26/04/2019

Acceptance date: 26/03/2019

Date deposited: 13/05/2019

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: Wiley-VCH Verlag


DOI: 10.15252/embj.2018100299


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