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

Jürgensen, Henrik J.; Nørregaard, Kirstine Sandal; Sibree, Megan; Santoni-Rugiu, Eric; Madsen, Daniel H.; Wassilew, Katharina; Krustrup, Dorrit; Garred, Peter; Bugge, Thomas H.; Engelholm, Lars H.; Behrendt, Niels

doi:10.1083/jcb.201802148

Cited by 15 publications

(20 citation statements)

References 62 publications

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“…It remains to be established whether MR-dependent, uPARAP-dependent, and MR- and uPARAP-independent collagen uptake is associated with differential macrophage functions or is involved in shaping macrophage phenotypes. In this regard, it should be noted that both receptors bind and endocytose other ligands besides collagen, including foreign and self-antigens for antigen presentation and collectins, and that collagen engagement may modulate these functions [ [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] ].…”

Section: Discussionmentioning

confidence: 99%

CCL2/MCP-1 signaling drives extracellular matrix turnover by diverse macrophage subsets

Jürgensen

Silva

Krigslund

et al. 2019

Matrix Biology Plus

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Macrophage plasticity, cellular origin, and phenotypic heterogeneity are perpetual challenges for studies addressing the biology of this pivotal immune cell in development, homeostasis, and tissue remodeling/repair. Consequently, a myriad of macrophage subtypes has been described in these contexts. To facilitate the identification of functional macrophage subtypes in vivo , here we used a flow cytometry-based assay that allows for detailed phenotyping of macrophages engaged in extracellular matrix (ECM) degradation. Of the five macrophage subtypes identified in the remodeling dermis by using this assay, collagen degradation was primarily executed by Ly6C − CCR2 + and Ly6C − CCR2 low macrophages via mannose receptor-dependent collagen endocytosis, while Ly6C + CCR2 + macrophages were the dominant fibrin-endocytosing cells. Unexpectedly, the CCL2/MCP1-CCR2 signaling axis was critical for both collagen and fibrin degradation, while collagen degradation was independent of IL-4Ra signaling. Furthermore, the cytokine GM-CSF selectively enhanced collagen degradation by Ly6C + CCR2 + macrophages. This study reveals distinct subsets of macrophages engaged in ECM turnover and identifies novel wound healing-associated functions for CCL2 and GM-CSF inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

CCL2/MCP-1 signaling drives extracellular matrix turnover by diverse macrophage subsets

Jürgensen

Silva

Krigslund

et al. 2019

Matrix Biology Plus

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“…Therefore, we surmised that under nutrient-scarce conditions of the pancreatic TME, ECM proteins in the milieu could be a source of amino acids for CAFs. It is well-established that stromal cells including fibroblasts internalize ECM proteins through uPARAP/Endo180 (encoded by the MRC2 gene) 26 , 27 and its expression is maximal in fibroblasts. However, there is a gap in knowledge regarding the role of ECM uptake by stromal fibroblasts in cancer.…”

Section: Resultsmentioning

confidence: 99%

Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours

et al. 2020

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“…However, although an increased number of apoptotic cells were detected in the single MT1-MMP knockout mice there was significantly increased apoptosis and a corresponding decrease in cell proliferation in the double knockout compared to either single knockout 44 . Further, up-regulation of Endo180 expression has been shown for pathological conditions such as liver fibrosis induced by CCl4 46 , lung fibrosis induced by bleomycin 47 and during wound healing 48,49 .…”

Section: Discussionmentioning

confidence: 99%

Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

Jungwirth

Weverwijk

Jenkins

et al. 2020

Preprint

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Profiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations.Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAFintrinsic contractility defect and reduced CAF viability which, coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.There is extensive functional evidence implicating cancer-associated fibroblasts (CAFs) in tumour progression, via their ability to deposit and remodel the extracellular matrix (ECM), to secrete pro-tumourigenic factors and by modulating the immune compartment 1-5 . However, there is also evidence that stromal fibroblasts can play a role in restraining tumour growth, for example by acting as a desmoplastic barrier to tumour cell invasion and by the recruitment of anti-tumour immune cells 6 .Consideration of how to limit the pro-tumourigenic functions of CAFs, whilst retaining their anti-tumourigenic role, has been hampered by a lack of understanding of the heterogeneity of CAFs within solid tumours and the paucity of specific markers to identify and functionally analyse different CAF subpopulations. Progress in addressing these shortcomings has come from a number of studies reporting single cell Page 3 of 47 sequencing of CAFs or analysis of CAF subsets which has revealed the diversity of fibroblast populations and provided important clues as to their origin and functional properties 7-14 .In this study, we explore the functional role of a CAF receptor, Endo180 (also known as uPARAP) encoded by the MRC2 gene. The 180 kDa Endo180 receptor comprises an N-terminal cysteine-rich domain, a fibronectin type II (FNII) domain that has been shown to bind collagens 15-19 , 8 C-type lectin-like domains (CTLDs), of which only CTLD2 displays Ca 2+ -dependent binding of sugars 20 , a single pass transmembrane domain and a cytoplasmic domain that interacts with components of the clathrin-mediated internalisation machinery to drive constitutive recycling between the plasma membrane and intracellular endosomes 21,22 . Although Endo180 is expressed by some sarcomas 23 , glioblastomas 24 and metaplastic breast cancers 25 , in most solid tumours of epithelial origin, expression of Endo180 is predominantly restricted to CAFs with little or no expressio...

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

Cited by 15 publications

References 62 publications

CCL2/MCP-1 signaling drives extracellular matrix turnover by diverse macrophage subsets

CCL2/MCP-1 signaling drives extracellular matrix turnover by diverse macrophage subsets

Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours

Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

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