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Immune regulation by fibroblasts in tissue injury depends on uPARAP-mediated uptake of collectins

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Collectins such as mannose-binding lectin (MBL) and surfactant protein D (SP-D) become temporarily deposited in extravascular compartments after tissue injury and perform immune-stimulatory or inflammation-limiting functions. However, their turnover mechanisms, necessary to prevent excessive tissue damage, are virtually unknown. In this study, we show that fibroblasts in injured tissues undertake the clearance of collectins by using the endocytic collagen receptor uPARAP. In cellular assays, several types of collectins were endocytosed in a highly specific uPARAP-dependent process, not shared by the closely related receptor MR/CD206. When introduced into dermis or bleomycin-injured lungs of mice, collectins MBL and SP-D were endocytosed and routed for lysosomal degradation by uPARAP-positive fibroblasts. Fibroblast-specific expression of uPARAP governed endogenous SP-D levels and overall survival after lung injury. In lung tissue from idiopathic pulmonary fibrosis patients, a strong up-regulation of uPARAP was observed in fibroblasts adjacent to regions with SP-D secretion. This study demonstrates a novel immune-regulatory function of fibroblasts and identifies uPARAP as an endocytic receptor in immunity.

Original languageEnglish
JournalJournal of Cell Biology
Volume218
Issue number1
Pages (from-to)333-349
Number of pages17
ISSN0021-9525
DOIs
Publication statusPublished - 7 Jan 2019

    Research areas

  • Animals, Bleomycin/administration & dosage, Bronchoalveolar Lavage Fluid/chemistry, Endocytosis, Fibroblasts/immunology, Gene Expression, Humans, Immunity, Innate, Interleukin-6/genetics, Lectins, C-Type/genetics, Lung Injury/chemically induced, Lung/immunology, Lysosomes/immunology, Mannose-Binding Lectin/genetics, Mannose-Binding Lectins/genetics, Membrane Glycoproteins/genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Proteolysis, Pulmonary Fibrosis/chemically induced, Pulmonary Surfactant-Associated Protein D/genetics, Receptors, Cell Surface/genetics, Survival Analysis

ID: 55803717