High Mobility Group Box-1 Promotes Inflammation-Induced Lymphangiogenesis via Toll-Like Receptor 4-Dependent Signalling Pathway

Han, Longhui; Zhang, Minglian; Wang, Meng Meng; Jia, Jinchen; Zhao, Miying; Fan, Yi‐Ming; Li, Xiaorong

doi:10.1371/journal.pone.0154187

Cited by 16 publications

(14 citation statements)

References 51 publications

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“…The pro-lymphatic role of TLR4 is consistent with previous reports of LPS- and HMGB1-induced inflammatory lymphangiogenesis [22,34,40], paclitaxel-induced tumor lymphangiogenesis [38], and decreased ability of TLR4-deficient mice to form lymphatic vessels compared with wild-type [35]. Both LPS- and paclitaxel-induced lymphangiogenesis have been linked to massive recruitment of BM-derived CD11b + myeloid cells expressing LEC-specific markers [22,34,38].…”

Section: Discussionsupporting

confidence: 91%

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: Discussionsupporting

confidence: 91%

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

et al. 2017

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“…In addition, AGEs-induced VEGF-A production in RGC-5 cells was suppressed by glycyrrhizin, an inhibitor of HMGB-1, suggesting that HMGB-1 was implicated in the angiogenesis of DR via regulating VEGF-A production [56, 82]. In line with the findings, a recent study demonstrated that HMGB-1 promoted lymphangiogenesis via TLR4/NF- Κ B/MMP9 signaling pathway, indicating that HMGB-1 may play an important role in diabetic retinopathy by modulating MMP9 [83]. …”

Section: Hmgb-1 and Dr (Diabetic Retinopathy)mentioning

confidence: 72%

High Mobility Group Box-1: A Missing Link between Diabetes and Its Complications

Chen

Xie

et al. 2016

Mediators of Inflammation

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High mobility group box-1 (HMGB-1), a damage-associated molecular pattern, can be actively or passively released from various cells under different conditions and plays a pivotal role in the pathogenesis of inflammation and angiogenesis-dependent diseases. More and more evidence suggests that inflammation, in addition to its role in progression of diabetes, also promotes initiation and development of diabetic complications. In this review, we focus on the role of HMGB-1 in diabetes-related complications and the therapeutic strategies targeting HMGB-1 in diabetic complications.

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“…An ILA model was established using previously described methods 35 – 37 . Briefly, a 2-mm corneal trephine was used to mark a circle on the centre of the cornea in the right eye.…”

Section: Methodsmentioning

confidence: 99%

Interleukin-33 promotes inflammation-induced lymphangiogenesis via ST2/TRAF6-mediated Akt/eNOS/NO signalling pathway

Han

Zhang

et al. 2017

Sci Rep

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The interplay between inflammation and lymphangiogenesis is mediated by various cytokines. However, most of these molecules and their associated mechanism are yet to be defined. Here, we explored the role of IL-33 in modulating inflammation-induced lymphangiogenesis (ILA) and its underlying mechanisms using an ILA mouse model and a lymphatic endothelial cell (LEC) line. Our results show that IL-33 promoted the proliferation, migration and tube formation of LECs and ILA in vivo. The pro-lymphangiogenic activity of IL-33 was abolished by ST2 blockage. In mechanisms, IL-33 induced the phosphorylation of Akt/eNOS to produce NO in LECs. The IL-33-induced Akt/eNOS activation was suppressed by the PI3K-specific-inhibitor wortmannin, and NO-production was inhibited by both wortmannin and the NO synthase-inhibitor NMA. Knock-down of ST2 or TRAF6 suppressed Akt/eNOS phosphorylation and NO production. The reduction of NO treated with wortmannin or NMA abolished the promoting effects of IL-33 on the chemotactic motility and tube formation of HDLECs. In vivo, IL-33-induced ILA was also impaired in eNOS−/− mice. In conclusion, our study is the first to show that IL-33 promotes inflammation-induced lymphangiogenesis via a ST2/TRAF6-mediated Akt/eNOS/NO signalling pathway. This findings may provide us more opportunities to treat inflammation and lymphangiogenesis associated diseases.

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High Mobility Group Box-1 Promotes Inflammation-Induced Lymphangiogenesis via Toll-Like Receptor 4-Dependent Signalling Pathway

Cited by 16 publications

References 51 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

High Mobility Group Box-1: A Missing Link between Diabetes and Its Complications

Interleukin-33 promotes inflammation-induced lymphangiogenesis via ST2/TRAF6-mediated Akt/eNOS/NO signalling pathway

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