Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution

Kataru, Raghu P.; Jung, Keehoon; Jang, Cholsoon; Yang, Hanseul; Schwendener, Reto A.; Baik, Jung Eun; Han, Seung Hyun; Alitalo, Kari; Koh, Gou Young

doi:10.1182/blood-2008-09-176776

Cited by 349 publications

(390 citation statements)

References 54 publications

(93 reference statements)

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“…Interestingly, macrophages decreased in inflammatory corneas after CXL, which should contribute to the regression of pathologic BVs and LVs in corneas, as macrophages play a key role in the induction of angiogenesis44, 45 and lymphangiogenesis46, 47, 48, 49 under pathological conditions in the cornea and in the maintenance of LVs 50. Furthermore, we also observed significant reduction in CD45 + leukocytes in suture‐induced inflammation in corneas after CXL treatment using riboflavin and UVA.…”

Section: Discussionmentioning

confidence: 53%

UV light crosslinking regresses mature corneal blood and lymphatic vessels and promotes subsequent high-risk corneal transplant survival

Hou

Tóth

et al. 2018

American Journal of Transplantation

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Immunologic graft rejection is the main complication after corneal transplant into pathologically prevascularized so‐called high‐risk eyes. The aim of this study was to evaluate whether ultraviolet (UV) light crosslinking can regress pathologic corneal blood and lymphatic vessels and thereby improve subsequent graft survival. Using the murine model of suture‐induced corneal neovascularization, we found that corneal crosslinking with UVA light and riboflavin regressed both preexisting blood and lymphatic vessels significantly via induction of apoptosis in vascular endothelial cells. In addition, macrophages and CD45+ cell counts were significantly reduced. Consistently, corneal crosslinking reduced keratocyte density and corneal thickness without affecting corneal nonvascular endothelial cells, iris, and lens depending on the crosslinking duration. Furthermore, using the murine model of corneal transplant, long‐term graft survival was significantly promoted (P < .05) and CD4+ CD25+FoxP3+ T regulatory cells were upregulated (P < .01) in high‐risk eyes preoperatively treated with crosslinking. Our results suggest UV light crosslinking as a novel method to regress both pathologic corneal blood and lymphatic vessels and to reduce CD45+ inflammatory cells. Furthermore, this study demonstrates for the first time that preoperative corneal crosslinking in prevascularized high‐risk eyes can significantly improve subsequent graft survival and may become a promising novel therapy in the clinic.

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Section: Discussionmentioning

confidence: 53%

UV light crosslinking regresses mature corneal blood and lymphatic vessels and promotes subsequent high-risk corneal transplant survival

Hou

Tóth

et al. 2018

American Journal of Transplantation

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“…In recent years, there has been growing appreciation that LN lymphangiogenesis can be a significant determinant of the immune response during inflammation (15,25,26). However, all of these studies focused on lymphangiogenesis occurring at early phases of inflammation and did not evaluate the exact location of the expanded lymphatic network within the LN.…”

Section: Discussionmentioning

confidence: 99%

“…To address this possibility, we next evaluated the effect of blocking lymphangiogenesis on lymphocyte egress from inflamed LNs. Because both VEGFR2-and VEGFR3-signaling pathways have been implicated in inflammatory LN lymphangiogenesis (15,21,25,26), we treated animals with neutralizing mAbs against VEGFR2 and VEGFR3 to inhibit lymphangiogenesis. Consistent with previous reports (15), blocking VEGFR2 and VEGFR3 signaling had no effect on preexisting lymphatic and blood vessels in resting LNs (data not shown).…”

Section: Immunization Induces Lymphangiogenesis In Dlnsmentioning

confidence: 99%

“…We examined whether VEGF-A and VEGF-C, essential growth factors for inflammation-induced lymphangiogenesis (15,21,25,26), may be involved in the prolonged LN lymphangiogenesis. ELISA analysis revealed that, compared with control LNs, VEGF-A and VEGF-C protein levels were highly elevated in homogenates of inflamed LNs at as early as 2 d postimmunization and remained elevated even at day 30 ( Fig.…”

Section: Ln Lymphangiogenesis Is Initiated and Sustained By Lymphangimentioning

confidence: 99%

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Expansion of Cortical and Medullary Sinuses Restrains Lymph Node Hypertrophy during Prolonged Inflammation

Tan

Yeo

Wong

et al. 2012

The Journal of Immunology

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During inflammation, accumulation of immune cells in activated lymph nodes (LNs), coupled with a transient shutdown in lymphocyte exit, results in dramatic cellular expansion. Counter-regulatory measures to restrain LN expansion must exist and may include re-establishment of lymphocyte egress to steady-state levels. Indeed, we show in a murine model that egress of lymphocytes from LNs was returned to steady-state levels during prolonged inflammation following initial retention. This restoration in lymphocyte egress was supported by a preferential expansion of cortical and medullary sinuses during late inflammation. Cortical and medullary sinus remodeling during late inflammation was dependent on temporal and spatial changes in vascular endothelial growth factor-A distribution. Specifically, its expression was restricted to the subcapsular space of the LN during early inflammation, whereas its expression was concentrated in the paracortical and medullary regions of the LN at later stages. We next showed that this process was mostly driven by the synergistic cross-talk between fibroblastic reticular cells and interstitial flow. Our data shed new light on the biological significance of LN lymphangiogenesis during prolonged inflammation and further underscore the collaborative roles of stromal cells, immune cells, and interstitial flow in modulating LN plasticity and function.

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“…Although VEGF-C is well-correlated with cancer metastasis, the requirement for tumor lymphangiogenesis is controversial, and there is evidence that VEGF-C can promote metastasis in the absence of tumor lymphangiogenesis [118][119][120][121][122][123]. VEGF-C can also attract macrophages [124] that can alter the tumor microenvironment to promote invasion. Furthermore, some tumor cells also express VEGFR-3 and thus may benefit from autocrine signaling of VEGF-C or -D [121,[125][126][127][128][129].…”

Section: Chronic Graft Rejectionmentioning

confidence: 99%

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

Lund

Swartz

2010

J Mammary Gland Biol Neoplasia

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Research in lymphatic biology and cancer immunology may soon intersect as emerging evidence implicates the lymphatics in the progression of chronic inflammation and autoimmunity as well as in tumor metastasis and immune escape. Like the blood vasculature, the lymphatic system comprises a highly dynamic conduit system that regulates fluid homeostasis, antigen transport and immune cell trafficking, which all play important roles in the progression and resolution of inflammation, autoimmune diseases, and cancer. This review presents emerging evidence that lymphatic vessels are active modulators of immunity, perhaps fine-tuning the response to adjust the balance between peripheral tolerance and immunity. This suggests that the tumor-associated lymphatic vessels and draining lymph node may be important in tumor immunity which in turn governs metastasis.

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Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution

Cited by 349 publications

References 54 publications

UV light crosslinking regresses mature corneal blood and lymphatic vessels and promotes subsequent high-risk corneal transplant survival

UV light crosslinking regresses mature corneal blood and lymphatic vessels and promotes subsequent high-risk corneal transplant survival

Expansion of Cortical and Medullary Sinuses Restrains Lymph Node Hypertrophy during Prolonged Inflammation

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

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