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

Manman Guo, Anetta Härtlova (Lead / Corresponding author), Marek Gierlinski, Alan Prescott, Josep Castellvi, Javier Hernandez Losa, Sine K. Petersen, Ulf A. Wenzel, Brian Dill, Christoph H. Emmerich, Santiago Ramon Y Cajal, David G. Russell, Matthias Trost (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Article numbere100299
Pages (from-to)1-15
Number of pages15
JournalEMBO Journal
Volume38
Issue number11
Early online date26 Apr 2019
DOIs
Publication statusPublished - 3 Jun 2019

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Scavenger Receptors
Macrophages
Interleukin-4
Inflammation
Chemical activation
Tissue homeostasis
Proteolysis
Phagosomes
Lipolysis
Scavenging
Proteome
Phagocytosis
Debris
Proteomics
Ovarian Neoplasms
Nutrients
Lipoproteins
Homeostasis
Anti-Inflammatory Agents
Switches

Keywords

  • macrophage scavenger receptor 1
  • phagosome
  • proteomics
  • scavenger receptor
  • tumour-associated macrophages

Cite this

Guo, M., Härtlova, A., Gierlinski, M., Prescott, A., Castellvi, J., Hernandez Losa, J., ... Trost, M. (2019). Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages. EMBO Journal, 38(11), 1-15. [e100299]. https://doi.org/10.15252/embj.2018100299
Guo, Manman ; Härtlova, Anetta ; Gierlinski, Marek ; Prescott, Alan ; Castellvi, Josep ; Hernandez Losa, Javier ; Petersen, Sine K. ; Wenzel, Ulf A. ; Dill, Brian ; Emmerich, Christoph H. ; Ramon Y Cajal, Santiago ; Russell, David G. ; Trost, Matthias. / Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages. In: EMBO Journal. 2019 ; Vol. 38, No. 11. pp. 1-15.
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abstract = "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.",
keywords = "macrophage scavenger receptor 1, phagosome, proteomics, scavenger receptor, tumour-associated macrophages",
author = "Manman Guo and Anetta H{\"a}rtlova and Marek Gierlinski and Alan Prescott and Josep Castellvi and {Hernandez Losa}, Javier and Petersen, {Sine K.} and Wenzel, {Ulf A.} and Brian Dill and Emmerich, {Christoph H.} and {Ramon Y Cajal}, Santiago and Russell, {David G.} and Matthias Trost",
note = "This work was funded by Medical Research Council UK (MC_UU_12016/5) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy (DSTT) (Boehringer Ingelheim, GlaxoSmithKline and Merck KGaA). ASH is funded by the Knut and Alice Wallenberg Foundation and the Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden. We would like to acknowledge Dundee Imaging Facility which is supported by the 'Wellcome Trust Technology Platform' award [097945/B/11/Z] and the 'MRC Next Generation Optical Microscopy' award [MR/K015869/1]. The School of Life Sciences Data Analysis Group and the Flow Cytometry Facility are funded by Wellcome Trust grants 097945/Z/11/Z and 081867/Z/06/Z, respectively.",
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Guo, M, Härtlova, A, Gierlinski, M, Prescott, A, Castellvi, J, Hernandez Losa, J, Petersen, SK, Wenzel, UA, Dill, B, Emmerich, CH, Ramon Y Cajal, S, Russell, DG & Trost, M 2019, 'Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages', EMBO Journal, vol. 38, no. 11, e100299, pp. 1-15. https://doi.org/10.15252/embj.2018100299

Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages. / Guo, Manman; Härtlova, Anetta (Lead / Corresponding author); Gierlinski, Marek; Prescott, Alan; Castellvi, Josep; Hernandez Losa, Javier; Petersen, Sine K.; Wenzel, Ulf A.; Dill, Brian; Emmerich, Christoph H.; Ramon Y Cajal, Santiago; Russell, David G.; Trost, Matthias (Lead / Corresponding author).

In: EMBO Journal, Vol. 38, No. 11, e100299, 03.06.2019, p. 1-15.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages

AU - Guo, Manman

AU - Härtlova, Anetta

AU - Gierlinski, Marek

AU - Prescott, Alan

AU - Castellvi, Josep

AU - Hernandez Losa, Javier

AU - Petersen, Sine K.

AU - Wenzel, Ulf A.

AU - Dill, Brian

AU - Emmerich, Christoph H.

AU - Ramon Y Cajal, Santiago

AU - Russell, David G.

AU - Trost, Matthias

N1 - This work was funded by Medical Research Council UK (MC_UU_12016/5) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy (DSTT) (Boehringer Ingelheim, GlaxoSmithKline and Merck KGaA). ASH is funded by the Knut and Alice Wallenberg Foundation and the Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden. We would like to acknowledge Dundee Imaging Facility which is supported by the 'Wellcome Trust Technology Platform' award [097945/B/11/Z] and the 'MRC Next Generation Optical Microscopy' award [MR/K015869/1]. The School of Life Sciences Data Analysis Group and the Flow Cytometry Facility are funded by Wellcome Trust grants 097945/Z/11/Z and 081867/Z/06/Z, respectively.

PY - 2019/6/3

Y1 - 2019/6/3

N2 - 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.

AB - 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.

KW - macrophage scavenger receptor 1

KW - phagosome

KW - proteomics

KW - scavenger receptor

KW - tumour-associated macrophages

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U2 - 10.15252/embj.2018100299

DO - 10.15252/embj.2018100299

M3 - Article

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VL - 38

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EP - 15

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

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ER -