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Cellular uptake of collagens and implications for immune cell regulation in disease

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Abstract

As the dominant constituent of the extracellular matrix (ECM), collagens of different types are critical for the structural properties of tissues and make up scaffolds for cellular adhesion and migration. Importantly, collagens also directly modulate the phenotypic state of cells by transmitting signals that influence proliferation, differentiation, polarization, survival, and more, to cells of mesenchymal, epithelial, or endothelial origin. Recently, the potential of collagens to provide immune regulatory signals has also been demonstrated, and it is believed that pathological changes in the ECM shape immune cell phenotype. Collagens are themselves heavily regulated by a multitude of structural modulations or by catabolic pathways. One of these pathways involves a cellular uptake of collagens or soluble collagen-like defense collagens of the innate immune system mediated by endocytic collagen receptors. This cellular uptake is followed by the degradation of collagens in lysosomes. The potential of this pathway to regulate collagens in pathological conditions is evident from the increased extracellular accumulation of both collagens and collagen-like defense collagens following endocytic collagen receptor ablation. Here, we review how endocytic collagen receptors regulate collagen turnover during physiological conditions and in pathological conditions, such as fibrosis and cancer. Furthermore, we highlight the potential of collagens to regulate immune cells and discuss how endocytic collagen receptors can directly regulate immune cell activity in pathological conditions or do it indirectly by altering the extracellular milieu. Finally, we discuss the potential collagen receptors utilized by immune cells to directly detect ECM-related changes in the tissues which they encounter.

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Acknowledgements

We thank Dr. Mary Jo Danton for critically reviewing this manuscript.

Funding

This study is supported by National Institute of Dental and Craniofacial Research (Intramural Research Program); Sundhed og Sygdom, Det Frie Forskningsråd (Grant Nos. 4092-00387B and DFF-4004-00340); Kræftens Bekæmpelse (Grant Nos. R90-A5989, R146-A9326-16-S2, R149-A9768-16-S47, R174-A11581-17-S52, R231-A13832, R222-A13103); Simon Fougner Hartmanns Familiefond; Region Hovedstadens forskningsfond; Novo Nordisk Fonden; Dansk Kræftforskningsfond.

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Authors and Affiliations

  1. Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center, University of Copenhagen, Ole Maaloesvej 5, 2200, Copenhagen N, Denmark

    Henrik J. Jürgensen, Sander van Putten, Kirstine S. Nørregaard, Lars H. Engelholm & Niels Behrendt

  2. Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA

    Thomas H. Bugge

  3. National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730, Herlev, Denmark

    Daniel H. Madsen

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  1. Henrik J. Jürgensen
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Jürgensen, H.J., van Putten, S., Nørregaard, K.S. et al. Cellular uptake of collagens and implications for immune cell regulation in disease. Cell. Mol. Life Sci. 77, 3161–3176 (2020). https://doi.org/10.1007/s00018-020-03481-3

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  • DOI: https://doi.org/10.1007/s00018-020-03481-3

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