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Triggering MSR1 Promotes JNK‐Mediated Inflammation in IL‐4

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Triggering MSR1 Promotes JNK‐Mediated Inflammation in IL‐4 Published online: April 26, 2019 Article Triggering MSR1 promotes JNK-mediated inflammation in IL-4-activated macrophages Manman Guo1,†,‡ , Anetta Härtlova1,2,3,4,†,* , Marek Gierlinski 5, Alan Prescott6, Josep Castellvi7, Javier Hernandez Losa7,8, Sine K Petersen3,4, Ulf A Wenzel3,4, Brian D Dill1, Christoph H Emmerich1, Santiago Ramon Y Cajal7,8, David G Russell9 & Matthias Trost1,2,** Abstract Introduction Alternatively activated M2 macrophages play an important role in Phagocytosis is a highly conserved process essential for host maintenance of tissue homeostasis by scavenging dead cells, cell defence and tissue remodelling. It involves the recognition of parti- debris and lipoprotein aggregates via phagocytosis. Using proteo- cles by a variety of cell surface receptors, followed by cargo process- mics, we investigated how alternative activation, driven by IL-4, ing and delivery to lysosomes via phagosome–lysosome fusion, modulated the phagosomal proteome to control macrophage process known as phagosome maturation. This leads to gradual function. Our data indicate that alternative activation enhances acidification of the phagosomal lumen and acquisition of digestive homeostatic functions such as proteolysis, lipolysis and nutrient enzymes required for the degradation of phagosomal cargo. There- transport. Intriguingly, we identified the enhanced recruitment of fore, phagocytosis is not only responsible for elimination of bacterial the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4-acti- pathogens, but also responsible for the clearance of apoptotic cells, vated macrophages. The recruitment of this signalling complex was cell debris and senescence cells and orchestrates the subsequent mediated through K63 polyubiquitylation of the macrophage scav- immune response (Rothlin et al, 2007; Murray & Wynn, 2011; enger receptor 1 (MSR1). Triggering of MSR1 in IL-4-activated Lemke, 2013, 2017). Central to this process is phagosome function. macrophages leads to enhanced JNK activation, thereby promoting If uncontrolled, the inappropriate clearance of apoptotic bodies can a phenotypic switch from an anti-inflammatory to a pro-inflamma- give rise to autoimmune diseases, atherosclerosis and cancer, while tory state, which was abolished upon MSR1 deletion or JNK inhibi- failure to ingest or kill pathogens can result in deadly infections tion. Moreover, MSR1 K63 polyubiquitylation correlated with the (Johnson & Newby, 2009; Nagata et al, 2010; Colegio et al, 2014; activation of JNK signalling in ovarian cancer tissue from human Arandjelovic & Ravichandran, 2015). Therefore, it is of great impor- patients, suggesting that it may be relevant for macrophage pheno- tance to understand which signalling pathways regulate phagocyto- typic shift in vivo. Altogether, we identified that MSR1 signals sis and phagosomal maturation. through JNK via K63 polyubiquitylation and provides evidence for It has recently been acknowledged that the phagosome serves as the receptor’s involvement in macrophage polarization. a signalling platform and interacts with innate immune signalling (Stuart et al, 2007; Martinez et al, 2011, 2015; Kagan, 2012; Heck- Keywords macrophage scavenger receptor 1; phagosome; proteomics; mann et al, 2017). However, whether phagosome-associated cell scavenger receptor; tumour-associated macrophages signalling is independent of its role in cargo degradation has not Subject Categories Post-translational Modifications, Proteolysis & Proteo- been well understood. Supporting this notion, recent proteomic mics; Signal Transduction; Immunology studies demonstrated that phagosomes are dynamic organelles that DOI 10.15252/embj.2018100299 | Received 1 August 2018 | Revised 22 March change their composition and function in response to infection or 2019 | Accepted 26 March 2019 inflammation (Trost et al, 2009; Boulais et al, 2010; Dill et al, 2015; The EMBO Journal (2019)e100299 Guo et al, 2015; Naujoks et al, 2016; Hartlova et al, 2018). While 1 MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK 2 Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK 3 Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden 4 Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 5 Data Analysis Group, School of Life Sciences, University of Dundee, Dundee, UK 6 Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK 7 Department of Pathology, Hospital Universitario Vall d’Hebron, Barcelona, Spain 8 Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Barcelona, Spain 9 Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA *Corresponding author. Tel: +46 31 786 6241; E-mail: [email protected] **Corresponding author. Tel: +44 191 2087009; E-mail: [email protected] †These authors contributed equally to this work ‡Present address: Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK ª 2019 The Authors. Published under the terms of the CC BY 4.0 license The EMBO Journal e100299 | 2019 1 of 15 Published online: April 26, 2019 The EMBO Journal Manman Guo et al the regulation of phagosomal maturation in so-called M1 inflamma- uptake behaviour, carboxylated microspheres may serve as a tory macrophages has been extensively studied, the mechanisms surrogate for apoptotic cells (Kiss et al, 2006). Next, we analysed facilitating phagosomal maturation in macrophages involved in the functional parameters of the phagosomal lumen. In these assays, tissue repair remain poorly understood (Balce et al, 2011). we use fluorescent probes that allow the measurement of proteolysis Th2-derived cytokines, such as interleukin-4 (IL-4) and inter- (a readout for maturation), acidification and lipolysis in real time leukin-13 (IL-13), induce a strong anti-inflammatory macrophage (Yates et al, 2005; Podinovskaia et al, 2013). Consistent with the phenotype, also called alternative-activated macrophages (M2). M2 previous reports, we observed enhanced proteolytic activity in macrophages and tissue-resident macrophages, which often phagosomes of M2 macrophages (Balce et al, 2011). Furthermore, resemble an M2-like state, clear cell debris and dead cells through we found that IL-4 increased phagosomal lipid degradation and phagocytosis. They are therefore essential for maintenance and facilitated phagosomal acidification (Fig 1C–E) indicating that IL-4 tissue homeostasis. M2 alternatively activated macrophages (AAMs) activation promotes phagosome maturation and the ability of inhibit inflammatory responses and promote angiogenesis and macrophages to degrade lipid-rich particles through phagosomes. tissue repair by synthetizing mediators required for collagen deposi- Altogether, these data indicate that that alternative activation tion, which is important for wound healing (Gordon & Martinez, increases the ability to take up and degrade apoptotic cells and other 2010). It has been shown that IL-4 enhanced phagosomal protein lipid-rich particles by increasing the degradative potential of degradation (Balce et al, 2011). Whether IL-4 regulates other phago- phagolysosomes from M2 (IL4) MΦs. somal functions, and through which molecular mechanisms, remains unclear. Quantitative proteomic analysis of phagosomes from IL-4 Here, we investigated the phagosome proteome of IL-4-activated alternatively activated macrophages macrophages. In line with the known role in homeostasis, the phagosome of AAMs has increased abilities to degrade incoming To obtain further molecular details about the changes on phago- apoptotic cells and transport the resulting nutrients. Furthermore, somes of M2 macrophages, we isolated highly pure phagosomes we demonstrate that the TAK1/MKK7/JNK signalling complex from M2 and M0 macrophages by floatation on a sucrose gradient showed an enhanced association with the phagosome upon IL-4 using carboxylated microspheres and analysed their proteomes by macrophage activation. The assembly of the signalling complex is quantitative LC-MS/MS (Fig 2A; Appendix Figs S1A–C and S2A; mediated through K63 polyubiquitylation. By combining K63-polyu- Desjardins et al, 1994; Peltier et al, 2017; Trost et al, 2009). biquitylation enrichment and mass spectrometry approaches, we Comparative analysis led to the identification of 20,614 distinct identified macrophage scavenger receptor 1 (MSR1) as the upstream peptides corresponding to 1,948 unique proteins across three inde- receptor that promotes the recruitment of the TAK1/MKK7/JNK pendent replicates at a false-discovery rate (FDR) of < 1%, of signalling complex to the phagosome. Triggering MSR1 induces JNK which 1,766 proteins were quantified in at least two of the three activation in M2 macrophages. This MSR1/JNK signalling pathway biological replicates. IL-4 activation induced strong changes to the activation leads to a M2/M1 macrophage phenotypic switch that is phagosome proteome with 121 proteins significantly up-regulated abolished in macrophages lacking MSR1. We demonstrate that and 62 proteins significantly down-regulated (twofold change, MSR1 is K63-ubiquitylated and signals through JNK in human P < 0.05; Fig 2B; Dataset EV1), some of which we validated by patient ovarian cancer, thus suggesting a potential role in human
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