Cathepsin D interacts with adenosine A2A receptors in mouse macrophages to modulate cell surface localization and inflammatory signaling

Skopál, Adrienn; Kéki, Tamás; Tóth, Péter; Csóka, Balázs; Koscsó, Balázs; Nemeth, Zoltan H; Antonioli, Luca; Ivessa, Andreas S.; Ciruela, Francisco; Virág, László; Haskó, György; Kókai, Endre

doi:10.1016/j.jbc.2022.101888

Cited by 6 publications

(14 citation statements)

References 64 publications

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“…Additionally, interferon regulatory genes (ISG15, IFI6, and IFI27), the classical complement pathway (C1QA, C1QB, and C1QC), and cathepsin genes (CTSA, CTSB, and CTSD) were highly expressed in TAMs ( Figures 3E, G ). Studies have shown that these genes are associated with tumor-promoting properties, including tumor invasion, angiogenesis, inflammation inhibition, and metastasis ( Vasiljeva et al, 2006 ; Bengsch et al, 2014 ; Akkari et al, 2016 ; Szekely et al, 2018 ; Roumenina et al, 2019 ; Park et al, 2020 ; Xu et al, 2021a ; Wang et al, 2021b ; Obradovic et al, 2021 ; Revel et al, 2022 ; Skopál et al, 2022 ). Based on functional gene expression, it was confirmed that these clusters had the function of the M2 phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…Our investigation identified a subset of CD163 + and TREM2 + TAMs, indicative of their inclination towards the M2 phenotype. Remarkably, these TAMs exhibited high expression of interferon regulatory genes (ISG15, IFI6, and IFI27) and cathepsin genes (CTSA, CTSB, and CTSD), known to contribute to pro-tumor properties such as invasion, angiogenesis, immune suppression, and metastasis ( Vasiljeva et al, 2006 ; Bengsch et al, 2014 ; Akkari et al, 2016 ; Szekely et al, 2018 ; Roumenina et al, 2019 ; Park et al, 2020 ; Xu et al, 2021b ; Wang et al, 2021b ; Obradovic et al, 2021 ; Revel et al, 2022 ; Skopál et al, 2022 ). The Mac_6 cluster displayed elevated expression of NR4A subfamily genes (NR4A1 and NR4A2), Kruppel-like factor family genes (KLF2 and KLF4), and heat shock protein family genes (HSPD1, HSPA1B, and HSP90AB1), signifying their crucial role as M2-like macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis

Wang

Liu

et al. 2023

Front. Genet.

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Introduction: Clear cell renal cell carcinoma (ccRCC) is associated with unfavorable clinical outcomes. To identify viable therapeutic targets, a comprehensive understanding of intratumoral heterogeneity is crucial. In this study, we conducted bioinformatic analysis to scrutinize single-cell RNA sequencing data of ccRCC tumor and para-tumor samples, aiming to elucidate the intratumoral heterogeneity in the ccRCC tumor microenvironment (TME).Methods: A total of 51,780 single cells from seven ccRCC tumors and five para-tumor samples were identified and grouped into 11 cell lineages using bioinformatic analysis. These lineages included tumor cells, myeloid cells, T-cells, fibroblasts, and endothelial cells, indicating a high degree of heterogeneity in the TME. Copy number variation (CNV) analysis was performed to compare CNV frequencies between tumor and normal cells. The myeloid cell population was further re-clustered into three major subgroups: monocytes, macrophages, and dendritic cells. Differential expression analysis, gene ontology, and gene set enrichment analysis were employed to assess inter-cluster and intra-cluster functional heterogeneity within the ccRCC TME.Results: Our findings revealed that immune cells in the TME predominantly adopted an inflammatory suppression state, promoting tumor cell growth and immune evasion. Additionally, tumor cells exhibited higher CNV frequencies compared to normal cells. The myeloid cell subgroups demonstrated distinct functional properties, with monocytes, macrophages, and dendritic cells displaying diverse roles in the TME. Certain immune cells exhibited pro-tumor and immunosuppressive effects, while others demonstrated antitumor and immunostimulatory properties.Conclusion: This study contributes to the understanding of intratumoral heterogeneity in the ccRCC TME and provides potential therapeutic targets for ccRCC treatment. The findings emphasize the importance of considering the diverse functional roles of immune cells in the TME for effective therapeutic interventions.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis

Wang

Liu

et al. 2023

Front. Genet.

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“…Peritoneal macrophage isolation from mouse strain C57BL6/J was performed according to Skopal et al, 2022 [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

“…RAW 264.7 macrophages, HEK-293 cell lines (ATCC, New York, NY, USA) expressing Flag-A 2A R (provided by Francesco Ciruela, Department of Pathology and Experimental Therapeutics, University of Barcelona, Spain), and primary IPMФ were cultured under the conditions described in Skopál et al, 2022 [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

“…Given that immune cells express high levels of A 2A Rs, we recently set out to identify A 2A R-interacting partners in macrophages. Our protein-protein interaction mapping identified Cathepsin D as an A 2A R interacting protein, the first such A 2A R-interacting protein to be identified in the macrophages [ 23 ]. Interestingly, stimulation of A 2A R in macrophages prevents the release of cytotoxic and proinflammatory mediators, leading to a reduction in tissue damage [ 24 , 25 , 26 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Adenosine A2A Receptor Activation Regulates Niemann–Pick C1 Expression and Localization in Macrophages

Skopál,

Ujlaki,

Gerencsér

et al. 2023

CIMB

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Adenosine plays an important role in modulating immune cell function, particularly T cells and myeloid cells, such as macrophages and dendritic cells. Cell surface adenosine A2A receptors (A2AR) regulate the production of pro-inflammatory cytokines and chemokines, as well as the proliferation, differentiation, and migration of immune cells. In the present study, we expanded the A2AR interactome and provided evidence for the interaction between the receptor and the Niemann–Pick type C intracellular cholesterol transporter 1 (NPC1) protein. The NPC1 protein was identified to interact with the C-terminal tail of A2AR in RAW 264.7 and IPMФ cells by two independent and parallel proteomic approaches. The interaction between the NPC1 protein and the full-length A2AR was further validated in HEK-293 cells that permanently express the receptor and RAW264.7 cells that endogenously express A2AR. A2AR activation reduces the expression of NPC1 mRNA and protein density in LPS-activated mouse IPMФ cells. Additionally, stimulation of A2AR negatively regulates the cell surface expression of NPC1 in LPS-stimulated macrophages. Furthermore, stimulation of A2AR also altered the density of lysosome-associated membrane protein 2 (LAMP2) and early endosome antigen 1 (EEA1), two endosomal markers associated with the NPC1 protein. Collectively, these results suggested a putative A2AR-mediated regulation of NPC1 protein function in macrophages, potentially relevant for the Niemann–Pick type C disease when mutations in NPC1 protein result in the accumulation of cholesterol and other lipids in lysosomes.

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Comprehensive proteomic analysis of the differential expression of 62 proteins following intracortical microelectrode implantation

Song,

Druschel,

Kasthuri

et al. 2024

Sci Rep

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Intracortical microelectrodes (IMEs) are devices designed to be implanted into the cerebral cortex for various neuroscience and neuro-engineering applications. A critical feature of IMEs is their ability to detect neural activity from individual neurons. Currently, IMEs are limited by chronic failure, largely considered to be caused by the prolonged neuroinflammatory response to the implanted devices. Over the past few years, the characterization of the neuroinflammatory response has grown in sophistication, with the most recent advances focusing on mRNA expression following IME implantation. While gene expression studies increase our broad understanding of the relationship between IMEs and cortical tissue, advanced proteomic techniques have not been reported. Proteomic evaluation is necessary to describe the diverse changes in protein expression specific to neuroinflammation, neurodegeneration, or tissue and cellular viability, which could lead to the further development of targeted intervention strategies designed to improve IME functionality. In this study, we have characterized the expression of 62 proteins within 180 μm of the IME implant site at 4-, 8-, and 16-weeks post-implantation. We identified potential targets for immunotherapies, as well as key pathways that contribute to neuronal dieback around the IME implant.

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Cathepsin D interacts with adenosine A2A receptors in mouse macrophages to modulate cell surface localization and inflammatory signaling

Cited by 6 publications

References 64 publications

Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis

Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis

Adenosine A2A Receptor Activation Regulates Niemann–Pick C1 Expression and Localization in Macrophages

Comprehensive proteomic analysis of the differential expression of 62 proteins following intracortical microelectrode implantation

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