Human Podoplanin-positive Monocytes and Platelets Enhance Lymphangiogenesis Through the Activation of the Podoplanin/CLEC-2 Axis

Hur, Jin; Jang, Jeong Hoon; Oh, Il Young; Choi, Jae Il; Yun, Ji Yeon; Kim, Joonoh; Choi, Young Eun; Ko, Seung Bum; Kang, Jin Gu; Kang, Jeehoon; Lee, Sang Eun; Lee, Hwan; Park, Young Bae; Kim, Hyo Soo

doi:10.1038/mt.2014.61

Cited by 25 publications

(20 citation statements)

References 34 publications

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“…Consistent with the monocytic origin, human LECP were successfully differentiated in vitro using monocytes from peripheral [27,32,33] or umbilical cord [24,54] blood and treatment with a VEGF-A/VEGF-C cocktail. Here, we provide evidence that mouse and human myeloid-monocytic cells can undergo similar pro-lymphatic reprogramming upon activation of TLR4.…”

Section: Discussionmentioning

confidence: 99%

Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4

et al. 2017

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BackgroundMyeloid-derived lymphatic endothelial cells (M-LECP) are induced by inflammation and play an important role in adult lymphangiogenesis. However, the mechanisms driving M-LECP differentiation are currently unclear. We previously showed that activation of Toll-like receptor-4 (TLR4) induces myeloid-lymphatic transition (MLT) of immortalized mouse myeloid cells. Here the goals were to assess the potential of different TLR4 ligands to induce pro-lymphatic reprogramming in human and mouse primary myeloid cells and to identify transcriptional changes regulating this process.Methodology/Principal findingsHuman and mouse myeloid cells were reprogrammed to the lymphatic phenotype by TLR4 ligands including lipopolysaccharide (LPS), recombinant high mobility group box 1 protein (HMGB1), and paclitaxel. TLR4 induced similar MLT in cells from mice of different strains and immune status. Commonly induced genes were detected by transcriptional profiling in human and mouse myeloid cells from either immunocompetent or immunodeficient mice. Shared trends included: (1) novel expression of lymphatic-specific markers vascular endothelial growth factor receptor-3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin (PDPN) largely absent prior to induction; (2) lack of notable changes in blood vessel-specific markers; (3) transient expression of VEGFR-3, but sustained increase of vascular endothelial growth factor-C (VEGF-C) and a variety of inflammatory cytokines; (4) dependency of VEGFR-3 upregulation and other LEC genes on NF-κB; and (5) novel expression of lymphatic-specific (e.g., PROX1) and stem/progenitor (e.g., E2F1) transcription factors known for their roles in adult and embryonic vascular formation. M-LECP generated by TLR4 ligands in vitro were functional in vivo as demonstrated by significantly increased lymphatic vessel density and lymphatic metastasis detected in orthotopic breast cancer models.Conclusions/SignificanceWe established a novel TLR4-dependent protocol for in vitro production of functionally competent M-LECP from primary human or mouse myeloid cells and identified many potential regulators of this process. This information can be further exploited for research and therapeutic purposes.

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Section: Discussionmentioning

confidence: 99%

Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4

et al. 2017

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“…We selected pdpn as a candidate. Indeed, this interaction molecule is expressed by human monocytes and RA synoviocytes . Furthermore, pdpn is expressed in hyperproliferative psoriatic epidermis , but its contribution to disease remains to be clarified further.…”

Section: Discussionmentioning

confidence: 99%

Role of podoplanin in the high interleukin-17A secretion resulting from interactions between activated lymphocytes and psoriatic skin-derived mesenchymal cells

Noack

Ndongo-Thiam

Miossec

2016

Clinical and Experimental Immunology

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Summary In the context of psoriasis, T helper type 17 (Th17) cells infiltrate the inflammatory site and interact with local mesenchymal cells, including skin fibroblasts. The aim of this work was to study the interactions of skin‐derived fibroblasts with peripheral blood mononuclear cells (PBMC) with a focus on the Th17 pathway and to identify a mechanism which leads to a high interleukin (IL)−17 secretion. A co‐culture system between PBMC and skin fibroblasts was developed. Healthy and patient PBMC were added to non‐lesional or lesional skin fibroblasts at a 5:1 ratio for 48 h in the presence or not of activation with phytohaemagglutinin (PHA). Monocytes were removed or not by adherence before the co‐culture. An anti‐podoplanin antibody was also used during the co‐culture. Cytokine production (IL‐8, IL‐6, IL‐1β and IL‐17) was measured by enzyme‐linked immunosorbent assay (ELISA) and cell staining (CD3, CD4, IL‐17 and podoplanin) by flow cytometry. Without T cell receptor (TCR) activation, IL‐8, IL‐6 and IL‐1β production increased in PBMC‐fibroblast co‐culture compared to PBMC alone. No additional effect was observed with TCR activation, with no difference in the Th17 cell percentage in activated‐PBMC alone or co‐cultured. Conversely, IL‐17 production was increased highly only in co‐cultures between control and patient activated‐PBMC and skin fibroblasts. Removal of monocytes decreased cytokine production, notably that of IL‐17. Addition of an anti‐podoplanin antibody decreased IL‐17 secretion by 60%. Interactions between resting PBMC and fibroblasts induce the IL‐8, IL‐6 and IL‐1β production. PBMC activation and cell interactions are critical for a high IL‐17 secretion. Podoplanin contributes largely to this massive IL‐17 secretion.

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“…However, whether the suppressive mechanism of lymphangiogenesis by platelets involves the interaction of podoplanin with CLEC-2 was not afforded. In contrast, Hur and coworkers [125] found that interaction of platelets with podoplanin-positive monocytes triggers lymphangiogenesis through activation of the podoplanin–CLEC-2 axis. The binding of CLEC-2 to the glycoprotein activates extracellular signal-regulated kinase (ERK) and AKT signaling pathways that induce transdifferentiation of monocytes to LECs and secretion of lymphangiogenic cytokines.…”

Section: Podoplanin In Inflammatory Lymphangiogenesismentioning

confidence: 94%

Podoplanin in Inflammation and Cancer

Quintanilla

Montero-Montero

Renart

et al. 2019

IJMS

179

182

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Podoplanin is a small cell-surface mucin-like glycoprotein that plays a crucial role in the development of the alveoli, heart, and lymphatic vascular system. Emerging evidence indicates that it is also involved in the control of mammary stem-cell activity and biogenesis of platelets in the bone marrow, and exerts an important function in the immune response. Podoplanin expression is upregulated in different cell types, including fibroblasts, macrophages, T helper cells, and epithelial cells, during inflammation and cancer, where it plays important roles. Podoplanin is implicated in chronic inflammatory diseases, such as psoriasis, multiple sclerosis, and rheumatoid arthritis, promotes inflammation-driven and cancer-associated thrombosis, and stimulates cancer cell invasion and metastasis through a variety of strategies. To accomplish its biological functions, podoplanin must interact with other proteins located in the same cell or in neighbor cells. The binding of podoplanin to its ligands leads to modulation of signaling pathways that regulate proliferation, contractility, migration, epithelial–mesenchymal transition, and remodeling of the extracellular matrix. In this review, we describe the diverse roles of podoplanin in inflammation and cancer, depict the protein ligands of podoplanin identified so far, and discuss the mechanistic basis for the involvement of podoplanin in all these processes.

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Human Podoplanin-positive Monocytes and Platelets Enhance Lymphangiogenesis Through the Activation of the Podoplanin/CLEC-2 Axis

Cited by 25 publications

References 34 publications

Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4

Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4

Role of podoplanin in the high interleukin-17A secretion resulting from interactions between activated lymphocytes and psoriatic skin-derived mesenchymal cells

Podoplanin in Inflammation and Cancer

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