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The Dynamic Uptake and Release of SOD3 from Intracellular Stores in Macrophages Modulates the Inflammatory Response

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The Dynamic Uptake and Release of SOD3 from Intracellular Stores in Macrophages Modulates the Inflammatory Response The dynamic uptake and release of SOD3 from intracellular stores in macrophages modulates the inflammatory response Hu, Lili; Zachariae, Elias D.; Larsen, Ulrike G.; Vilhardt, Frederik; Petersen, Steen V. Published in: Redox Biology DOI: 10.1016/j.redox.2019.101268 Publication date: 2019 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Hu, L., Zachariae, E. D., Larsen, U. G., Vilhardt, F., & Petersen, S. V. (2019). The dynamic uptake and release of SOD3 from intracellular stores in macrophages modulates the inflammatory response. Redox Biology, 26, [101268]. https://doi.org/10.1016/j.redox.2019.101268 Download date: 25. Sep. 2021 Redox Biology 26 (2019) 101268 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox The dynamic uptake and release of SOD3 from intracellular stores in macrophages modulates the inflammatory response T Lili Hua, Elias D. Zachariaea, Ulrike G. Larsena, Frederik Vilhardtb, Steen V. Petersena,* a Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark b Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200, Copenhagen N, Denmark ARTICLE INFO ABSTRACT Keywords: Superoxide dismutase 3 (SOD3) is an extracellular enzyme with the capacity to modulate extracellular redox Superoxide dismutase 3 (SOD3) conditions by catalyzing the dismutation of superoxide to hydrogen peroxide. In addition to synthesis and re- Macrophage lease of this extracellular protein via the secretory pathway, several studies have shown that the protein also Internalization localizes to intracellular compartments in neutrophils and macrophages. Here we show that human macrophages Secretion release SOD3 from an intracellular compartment within 30 min following LPS stimulation. This release acutely Extracellular redox regulation increases the level of SOD3 on the cell surface as well as in the extracellular environment. Generation of the LRP1 intracellular compartment in macrophages is supported by endocytosis of extracellular SOD3 via the LDL re- ceptor-related protein 1 (LRP1). Using bone marrow-derived macrophages established from wild-type and − − SOD3 / mice, we further show that the pro-inflammatory profile established in LPS-stimulated cells is altered in the absence of SOD3, suggesting that the active release of this protein affects the inflammatory response. The internalization and acute release from stimulated macrophages indicates that SOD3 not only functions as a passive antioxidant in the extracellular environment, but also plays an active role in modulating redox signaling to support biological responses. 1. Introduction oxidative stress, but also partakes in the control of the inflammatory response in basal conditions. The association between SOD3 and the The enzymatic activity of extracellular superoxide dismutase (EC- inflammatory response has also been established in several in vivo − − SOD or SOD3)1 supports the dismutation of superoxide to hydrogen models using SOD3 / mice or mice overexpressing SOD3 establishing peroxide. In addition, the protein holds the capacity to bind cell surface that the protein acts as an anti-inflammatory mediator [11–17]. proteoglycans and constituents of the extracellular matrix via a posi- Moreover, studies have suggested a role of SOD3 in regulating tran- tively charged C-terminal region (ECM-binding region) [1]. Based on scription factor activity [18,19] as well as affecting signal transduction these properties, SOD3 has been described as an antioxidant im- by regulating the activity of protein tyrosine phosphatases [20]. It is mobilized in the extracellular space, serving to protect cells and bio- thus evident that SOD3 is not only a passive antioxidant providing molecules against superoxide-induced damage [2–6] as well as pro- extracellular protection against superoxide-mediated damage but also tecting the bioactivity of nitric oxide by inhibiting the diffusion limited participates actively in regulating diverse biological functions. reaction between NO and superoxide [7–9]. Interestingly, in the ab- Transcription of the SOD3 gene is epigenetically regulated by both sence of exogenous oxidative stress, mice subjected to conditional ta- methylation of the promotor region as well as by histone acetylation/ moxifen-induced SOD3 KO developed severe lung injury characterized deacetylation controlling gene accessibility [21–25]. These elements by inflammatory cell infiltration and presented a significant increase in are likely to explain the finding that SOD3 protein can be detected in mortality [10]. This study suggests that SOD3 not only serves to protect only a limited amount of cell types including pulmonary fibroblasts and biomolecules against superoxide-induced damage under conditions of epithelial cells as well as vascular smooth muscle cells [26–30]. Indeed, * Corresponding author. Department of Biomedicine, Høegh-Guldbergsgade 10, DK-8000, Aarhus C, Denmark. E-mail address: [email protected] (S.V. Petersen). 1 We suggest that the nomenclature of superoxide dismutase isozymes in mammals should be SOD1, SOD2 and SOD3, representing Cu/Zn-SOD, Mn-SOD and EC- SOD. This nomenclature is increasingly used in the literature. Moreover, the latter notion mix the type of associated metals (Cu/Zn-SOD, Mn-SOD) with spatial localization (EC-SOD), which makes this nomenclature inconsistent. In addition, although SOD3 is processed through the secretory pathway, our data and data by others show that the distribution of SOD3 may be more complex and not only associated with the extracellular space. https://doi.org/10.1016/j.redox.2019.101268 Received 20 May 2019; Received in revised form 24 June 2019; Accepted 1 July 2019 Available online 02 July 2019 2213-2317/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). L. Hu, et al. Redox Biology 26 (2019) 101268 the lack of SOD3 expression in human pulmonary artery endothelial 2.1. Cell culture cells has been shown to rely on epigenetic regulation, as the expression could be induced by demethylation of the promotor region as well as Human monocytes were isolated from buffy coats using Ficoll- modulation of histone acetylation [22,31]. Moreover, the expression paque™ PLUS (GE Healthcare). Briefly, the buffy coat material was di- can be upregulated by cytokines including IFNγ and IL-4 whereas TNFα luted in PBS (without Mg2+ and Ca2+) containing 2 mM EDTA and the downregulate the expression [22,32,33]. The transcriptional regulation diluted material layered on top of a Ficoll-paque™ PLUS cushion and of SOD3 is an adaptive response that may develop over several days centrifuged for 30 min at 1.000×g. The established layer of lympho- [32], and cannot be mobilized for an acute response. cytes and monocytes was removed and subsequently washed twice in Several studies have shown that SOD3 is present in inflammatory PBS and seeded in 10 cm petri dishes in RPMI 1640 containing 2% cells including macrophages and neutrophils [34–37]. We have recently human serum, 100 U/ml penicillin and 100 μg/ml streptomycin shown that SOD3 is only released from macrophages and neutrophils (hsRPMI). Monocytes were allowed to adhere for 3 h where after upon cellular stimulation with LPS and fMLF, respectively [36,37]. medium was removed and cells wash twice with PBS before receiving Moreover, LPS was also found to induce secretion of SOD3 from iso- hsRPMI containing 20 ng/ml M-CSF. After overnight incubation, 50% lated astrocytes [38]. Interestingly, the secretion was not reflected by of the medium was exchanged for fresh medium, and the cells allowed an increase in the level of SOD3 mRNA, suggesting that the release was to differentiate into M0 macrophages and used after 7–10 days of dif- established from a preformed population. High resolution analyses of ferentiation. isolated neutrophils and macrophages by electron microscopy show that SOD3 is present in intracellular vesicles [36,39]. Since SOD3 is 2.2. SDS-PAGE and western blotting synthesized in the secretory pathway and secreted as an extracellular fi protein, this nding indicates that SOD3 is internalized from the ex- SDS-PAGE analysis was performed using uniform 10% poly- tracellular space to be stored in an intracellular compartment and only acrylamide gels and the glycine/2-amino-2-methyl-1,3-propanediol- released upon stimulation. In concert, our data suggest that the sti- HCl buffer system described previously [43]. Reducing conditions were mulated release of SOD3 represents an acute response providing SOD obtained by boiling samples in the presence of 0.5% (w/v) SDS and activity to the extracellular environment. 50 mM dithiothreitol prior to electrophoresis. For Western blotting, To understand the control of SOD3 activity in the extracellular separated proteins were electrophoretically transferred to a poly- space, we have characterized the cellular distribution of SOD3 in vinylidene difluroride membrane for 1 h at 150 mA in 10 mM 3-(cy- macrophages in detail. We show that SOD3 is released within 30 min of clohexylamino)-1-propane sulfonic acid (pH 11) containing 10% (v/v) α macrophage stimulation, correlating with the kinetics of TNF release ethanol [44]. The membranes were blocked with 5% (w/v) skimmed [40]. Moreover, we show that SOD3 is mobilized from pre-formed in- milk in 20 mM Tris-HCl (pH 7.4), 137 mM NaCl supplemented with tracellular vesicles likely established by receptor-mediated endocytosis 0.1% (v/v) Tween 20 (TBST) and SOD3 protein detected by using a supported by the interaction between LDL receptor-related protein 1 rabbit anti-SOD3 antiserum. Blots were developed by ECL using per- (LRP1) and SOD3 [41]. Analysis of the functional impact of this sti- oxidase-conjugated goat anti-rabbit Ig and data acquired using an Im- mulated release was evaluated using macrophages isolated from wild- − − ageQuant LAS 4000 instrument (GE Healthcare). type and SOD3 / mice, and showed that the absence of SOD3 sig- nificantly increased the level of secreted pro-inflammatory cytokines and chemokines, including CXCL2 and sICAM-1. Collectively, our data 2.3.
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