Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation

Maisel, Katharina; Hrusch, Cara L.; Medellin, Jorge Emiliano Gomez; Potin, Lambert; Chapel, David; Nurmi, Harri; Camacho, Daniel F.; Gleyzer, Rachel; Alitalo, Kari; Sperling, Anne I.

doi:10.1038/s41385-020-0308-4

Cited by 11 publications

(8 citation statements)

References 61 publications

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“…Such a pathogenic effect of neolymphatics was observed in cornea, liver, or kidney allograft rejection ( 79 – 81 ), and antilymphangiogenesis therapy can prolong graft survival ( 82 , 83 ). Similarly, allergen-induced conjunctival or airway lymphangiogenesis can promote antigen presentation and the subsequent allergy-specific inflammatory cascade and clinical signs ( 27 , 84 ). By contrast, lymphatic vessels are capable of ameliorating chronic inflammation and edema in the bacterial keratitis model ( 85 ), reinforcing the notion that lymphangiogenesis plays context-dependent roles in different disease and tissue settings.…”

Section: Discussionmentioning

confidence: 99%

Alkali injury–induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation

Liu,

Shi

et al. 2024

JCI Insight

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Inflammatory lymphangiogenesis is intimately linked to immune regulation and tissue homeostasis. However, current evidence has suggested that classic lymphatic vessels are physiologically absent in intraocular structures. Here, we show that neolymphatic vessels were induced in the iris after corneal alkali injury (CAI) in a VEGFR3-dependent manner. Cre-loxP –based lineage tracing revealed that these lymphatic endothelial cells (LECs) originate from existing Prox1 + lymphatic vessels. Notably, the ablation of iridial lymphangiogenesis via conditional deletion of VEGFR3 alleviated the ocular inflammatory response and pathological T cell infiltration. Our findings demonstrate that iridial neolymphatics actively participate in pathological immune responses following injury and suggest intraocular lymphangiogenesis as a valuable therapeutic target for the treatment of ocular inflammation.

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Section: Discussionmentioning

confidence: 99%

Alkali injury–induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation

Liu,

Shi

et al. 2024

JCI Insight

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“…For instance, lymphatic vessels play a direct role in the maturation of T cells ( 65 , 66 ), and dysfunction of the lymphatics leads to the persistence of immune cells and mediators in tissues, resulting in a chronic inflammation and tissue damage ( 67 ). Moreover, recent papers reported that the VEGFR-3 signaling, promoting lymphangiogenesis, is also important to both initiate the acute innate and adaptive immune responses and to regulate the chronic T cell-mediated response (by changing the Treg/Th2 balance), suggesting an immunomodulatory role for this signaling ( 68 , 69 ).…”

Section: Discussionmentioning

confidence: 99%

Developmental Dysfunction of the Central Nervous System Lymphatics Modulates the Adaptive Neuro-Immune Response in the Perilesional Cortex in a Mouse Model of Traumatic Brain Injury

et al. 2021

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RationaleThe recently discovered meningeal lymphatic vessels (mLVs) have been proposed to be the missing link between the immune and the central nervous system. The role of mLVs in modulating the neuro-immune response following a traumatic brain injury (TBI), however, has not been analyzed. Parenchymal T lymphocyte infiltration has been previously reported as part of secondary events after TBI, suggestive of an adaptive neuro-immune response. The phenotype of these cells has remained mostly uncharacterized. In this study, we identified subpopulations of T cells infiltrating the perilesional areas 30 days post-injury (an early-chronic time point). Furthermore, we analyzed how the lack of mLVs affects the magnitude and the type of T cell response in the brain after TBI.MethodsTBI was induced in K14-VEGFR3-Ig transgenic (TG) mice or in their littermate controls (WT; wild type), applying a controlled cortical impact (CCI). One month after TBI, T cells were isolated from cortical areas ipsilateral or contralateral to the trauma and from the spleen, then characterized by flow cytometry. Lesion size in each animal was evaluated by MRI.ResultsIn both WT and TG-CCI mice, we found a prominent T cell infiltration in the brain confined to the perilesional cortex and hippocampus. The majority of infiltrating T cells were cytotoxic CD8+ expressing a CD44hiCD69+ phenotype, suggesting that these are effector resident memory T cells. K14-VEGFR3-Ig mice showed a significant reduction of infiltrating CD4+ T lymphocytes, suggesting that mLVs could be involved in establishing a proper neuro-immune response. Extension of the lesion (measured as lesion volume from MRI) did not differ between the genotypes. Finally, TBI did not relate to alterations in peripheral circulating T cells, as assessed one month after injury.ConclusionsOur results are consistent with the hypothesis that mLVs are involved in the neuro-immune response after TBI. We also defined the resident memory CD8+ T cells as one of the main population activated within the brain after a traumatic injury.

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“…As mentioned previously, regulatory T-cells are dysfunctional in many auto-immune diseases and manipulation of MHCII presentation by LECs could be a strategy to abrogate dysfunction. In a dust-mite allergy model, VEGFR3 antagonism exacerbated the allergic Th2 memory response in the lungs [32 ▪ ]. This was attributed to increased accumulation of naive T cells and decreased regulatory T cells in the draining lymph node, possibly due to lower lung tissue CCL21 without concomitant decreased CCL21 in the draining lymph node.…”

Section: Lymph Node Lymphatics Function Regulation and Therapeutic Ta...mentioning

confidence: 95%

Advances in understanding and examining lymphatic function: relevance for understanding autoimmunity

Ambler

Santambrogio

2021

Current Opinion in Rheumatology

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Purpose of reviewThe aim of this review is to give insights into how novel lymphatics functions may influence autoimmunity. Recent findingsThe lymphatic system connects peripheral tissues to draining lymph nodes to regulate adaptive immunity and directly interfaces with leukocytes in lymph vessels and in the lymph node. Here, we discuss recent findings showing evidence of dysfunctional lymphatics in autoimmune disease, new understanding of how afferent lymphatic regulation can modulate immunity, lymph node lymphatic heterogeneity and how these lymphatics can directly modulate lymphocyte function, how this understanding can be harnessed for new therapeutics, and new tools for the investigation of lymphatic and immune biology. SummaryLymphatics have an active role in the regulation of inflammation and the adaptive immune response. Here, we review recent findings in lymphatics biology in peripheral tissues and lymph nodes and emphasize the relevance for better understanding autoimmune diseases.

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Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation

Cited by 11 publications

References 61 publications

Alkali injury–induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation

Alkali injury–induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation

Developmental Dysfunction of the Central Nervous System Lymphatics Modulates the Adaptive Neuro-Immune Response in the Perilesional Cortex in a Mouse Model of Traumatic Brain Injury

Advances in understanding and examining lymphatic function: relevance for understanding autoimmunity

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