The inflammatory response of lymphatic endothelium

Aebischer, David; Iolyeva, Maria; Halin, Cornelia

doi:10.1007/s10456-013-9404-3

Cited by 63 publications

(61 citation statements)

References 110 publications

(230 reference statements)

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“…4) highlights the potential importance of this receptor-ligand pair as a therapeutic target. While many inflammatory signals upregulate lymphatic CCL21 at effector sites, its expression levels as well as that of other lymphatically expressed chemokines and adhesion molecules are strongly stimulus-dependent during inflammation (reviewed in (36)). Since we show that diminished T cell egress exacerbates inflammation, future studies will be critical to reveal the regulation of CCL21 on lymphatic endothelial cells and CCR7 on tissue-infiltrating T cells in addition to identifying alternative tissue exit receptors active in different types of inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Other examples demonstrate that lymphatic vessel function and activation ( e.g. by VEGF-C and VEGF-D) decrease inflammation by expanding the lymphatic network and enhancing the drainage of fluid and inflammatory mediators from the tissue (21, 36). Thus, afferent lymphatics fulfill a key anti-inflammatory role by counteracting the function of blood vascular endothelial cells, which allow for the entry of pro-inflammatory cells, fluid and mediators from the blood into the tissue.…”

Section: Discussionmentioning

confidence: 99%

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Effector T Cell Egress via Afferent Lymph Modulates Local Tissue Inflammation

Gómez

Diehl

Crosby

et al. 2015

The Journal of Immunology

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Memory/effector T cells recirculate through extralymphoid tissues by entering from blood and egressing via afferent lymph. While T cell entry into effector sites is key to inflammation, the relevance of T cell egress to this process is unknown. Here we found that antigen recognition at the effector site reduced the tissue egress of pro-inflammatory Th1 cells in a mouse model of delayed hypersensitivity. Transgenic expression of ‘tissue exit receptor’ CCR7 enhanced lymphatic egress of antigen-sequestered Th1 cells from the inflamed site and ameliorated inflammation. In contrast, lack of CCR7 on Th1 cells diminished their tissue egress while enhancing inflammation. Lymph-borne Th1 and Th17 cells draining the inflamed skin of sheep migrated toward the CCR7 ligand CCL21, suggesting the CCR7-CCL21 axis as a physiological target in regulating inflammation. In conclusion, exit receptors can be targeted to modulate T cell dwell time and inflammation at effector sites, revealing T cell tissue egress as a novel control point of inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effector T Cell Egress via Afferent Lymph Modulates Local Tissue Inflammation

Gómez

Diehl

Crosby

et al. 2015

The Journal of Immunology

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“…In addition, lymphatic vessels make several key contributions to metastasis, which likely include the targeted recruitment of cancer cells toward lymphatic vessels and LNs, the provision of a cancer stem cell niche, and the modulation of antitumor immune responses at the level of the primary tumor and the metastatic LN. Within most non-neoplastic tissues, lymphatic vessels are a major source of the chemokine CCL21, which binds to the CCR7 receptor on activated DCs, thereby recruiting them toward the lymphatic vasculature and finally toward the draining LNs to initiate immune responses (53). In in vitro studies, enhanced lymphatic flow has been found to upregulate CCL21 production by the lymphatic endothelium (54).…”

Section: Lymphatic Vessel Effects On Metastatic Tumor Cellsmentioning

confidence: 99%

Mechanisms of lymphatic metastasis

Karaman¹,

Detmar²

2014

J. Clin. Invest.

463

417

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Malignant tumors release growth factors such as VEGF-C to induce lymphatic vessel expansion (lymphangiogenesis) in primary tumors and in draining sentinel LNs, thereby promoting LN metastasis. Surprising recent evidence suggests that lymphatic vessels do not merely represent passive channels for tumor spread, but that they may actively promote tumor cell recruitment to LNs, cancer stem cell survival, and immune modulation. New imaging approaches allow the sensitive visualization of the earliest LN metastases and the quantitative, noninvasive measurement of the function of tumor-draining lymphatic vessels, with potential applications in the development of biomarkers for prognosis and measurement of therapeutic response.Cancer metastasis, the dissemination of cancer cells from the primary tumor to organs, where they initiate malignant growth, is the primary cause of cancer-related deaths. There has been a plethora of studies addressing the mechanisms of tumor metastasis via the bloodstream to distant organs; however, the majority of epithelial cancers first develop metastatic growth by spreading via lymphatic vessels to their draining LNs. Indeed, the detection of metastases within the sentinel LNs (SLNs; the first LNs into which a tumor drains) has major prognostic implications for patient survival and often also determines the choice of adjuvant therapies (1). Despite the obvious clinical importance of LN metastasis, the mechanisms leading to tumor spread via lymphatic vessels have remained unknown for decades. In fact, the prevailing view suggested that lymphatic vessels only play a passive role in tumor metastasis, serving merely as channels for tissue-invading tumor cells. The limited knowledge in this field was due to the relatively low scientific interest in lymphatic vessels as compared to the blood vasculature, the lack of reliable molecular markers to distinguish between lymphatic and blood vessels, the absence of identified growth factors for the lymphatic system, and the paucity of suitable experimental models to study and quantify LN metastasis. During the last 15 years, however, there has been substantial progress in the field of lymphatic vessel biology, which has rapidly lead to the recognition of the lymphatic vascular system as a major player involved in a multitude of human diseases (2). In this article, we will discuss the major discoveries made by our laboratory and many other researchers that have led to the recognition of a major role for the lymphatic vasculature in promoting cancer metastasis and to the new concepts of tumor-associated and LN lymphangiogenesis with a specific focus on the development of new strategies to image and therapeutically target the lymphatic system in cancer.

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“…Whilst lymph node spread of cancer has been known for decades, more recent evidence has implicated the lymphatics not simply as passive highways for tumour cell spread but also as facilitators in many other processes, including the active recruitment of tumour cells to local and distal lymph nodes 162 through mechanisms such as CCL21–CCR7 signalling 163, 164 , promoting the survival of metastasising cancer stem cells via CXCL12–CXCR4 signalling 165, 166 , and modulating the host inflammatory response to alter tumour immune surveillance 167– 170 . Inflammation is a critical component of tumour progression, and inflammatory cells are seen as an indispensable participant in progression.…”

Section: Going With the Flow: Intravasation Into Blood And Lymphaticsmentioning

confidence: 99%

Recent advances in understanding the complexities of metastasis

et al. 2018

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Tumour metastasis is a dynamic and systemic process. It is no longer seen as a tumour cell-autonomous program but as a multifaceted and complex series of events, which is influenced by the intrinsic cellular mutational burden of cancer cells and the numerous bidirectional interactions between malignant and non-malignant cells and fine-tuned by the various extrinsic cues of the extracellular matrix. In cancer biology, metastasis as a process is one of the most technically challenging aspects of cancer biology to study. As a result, new platforms and technologies are continually being developed to better understand this process. In this review, we discuss some of the recent advances in metastasis and how the information gleaned is re-shaping our understanding of metastatic dissemination.

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The inflammatory response of lymphatic endothelium

Cited by 63 publications

References 110 publications

Effector T Cell Egress via Afferent Lymph Modulates Local Tissue Inflammation

Effector T Cell Egress via Afferent Lymph Modulates Local Tissue Inflammation

Mechanisms of lymphatic metastasis

Recent advances in understanding the complexities of metastasis

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