VEGF-C/VEGFR-3 signalling in macrophages ameliorates acute lung injury

Yamashita, Masahiro; Niisato, Miyuki; Kawasaki, Yasushi; Karaman, Sinem; Robciuc, Marius R.; Shibata, Yuji; Ishida, Yoshiteru; Nishio, Ryo; Masuda, Tomoyuki; Sugai, Tamotsu; Ono, M.; Tuder, Rubin M.; Alitalo, Kari; Yamauchi, Kohei

doi:10.1183/13993003.00880-2021

Cited by 22 publications

(11 citation statements)

References 38 publications

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“…Vascular endothelial growth factor A (VEGF-A) signaling plays critical roles in increasing vascular permeability; however Spry4 has been shown to negatively regulate VEGF-A pathway [ 44 , 45 ]. The protective effects of macrophage Spry4 deficiency against sepsis-induced ALI might be associated with the induction of VEGF-C pathway [ 46 ]. In addition, Spry4 silence facilitated the migration and adhesion of endothelial and epithelial cells that may also enhancing the reparative function of the lung during sepsis [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Macrophage Sprouty4 deficiency diminishes sepsis-induced acute lung injury in mice

Chen¹,

Chen²,

Liu³

et al. 2022

Redox Biology

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Section: Discussionmentioning

confidence: 99%

Macrophage Sprouty4 deficiency diminishes sepsis-induced acute lung injury in mice

Chen¹,

Chen²,

Liu³

et al. 2022

Redox Biology

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“…However, while scRNA‐sequencing data showed that the Flt4 expression level was minuscule in chondrocytes from mice with PTOA and patients with OA (Supplementary Figure 10, available on the Arthritis & Rheumatology website at https://doi.org/10.1002/art.42441), evidence of VEGFR‐3 expression was previously reported in the articular cartilage from OA patients who had undergone knee replacement and in the cartilage–subchondral bone interface (40,41). In addition, VEGF‐C can affect osteoclasts (42) and macrophages (43) via its interaction with VEGFR‐3. Thus, VEGF‐C may exert effects directly on articular cartilage, bone tissue, or immune cells in addition to the SLS, which requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Targeting Synovial Lymphatic Function as a Novel Therapeutic Intervention for Age‐Related Osteoarthritis in Mice

Lin

Bell

Catheline

et al. 2023

Arthritis & Rheumatology

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Objective. The synovial lymphatic system (SLS) removes catabolic factors from the joint. Vascular endothelial growth factor C (VEGF-C) and its receptor, VEGFR-3, are crucial for lymphangiogenesis. However, their involvement in age-related osteoarthritis (OA) is unknown. This study was undertaken to determine whether the SLS and the VEGF-C/VEGFR-3 pathway contribute to the development and progression of age-related OA, using a murine model of naturally occurring joint disease.Methods. SLS function was assessed in the knees of young (3-month-old) and aged (19-24-month-old) male and female C57BL/6J mice via a newly established in vivo IVIS-dextran imaging approach, which, in addition to histology, was used to assess the effects of VEGF-C treatment on SLS function and OA pathology in aged mice. RNA-sequencing of synovial tissue was performed to explore molecular mechanisms of the disease in the mouse knee joints.Results. Results showed that aged mice had impaired SLS function, including decreases in joint clearance (mean T 1/2 of signal intensity clearance, 2.8 hours in aged mice versus 0.5 hours in young mice; P < 0.0001), synovial influx (mean ± SD 1.7 ± 0.8% in aged mice versus 4.1 ± 1.9% in young mice; P = 0.0004), and lymph node draining capacity (mean ± SD epifluorescence total radiant intensity ([photons/second]/[μW/cm 2 ]) 1.4 ± 0.8 in aged mice versus 3.7 ± 1.2 in young mice; P < 0.0001). RNA-sequencing of the synovial tissue showed that Vegf-c and Vegfr3 signaling genes were decreased in the synovium of aged mice. VEGF-C treatment resulted in improvements in SLS function in aged mice, including increased percentage of signal intensity joint clearance (mean ± SD 63 ± 9% in VEGF-C-treated aged mice versus 52 ± 15% in vehicle-treated aged mice; P = 0.012), increased total articular cartilage cross-sectional area (mean ± SD 0.38 ± 0.07 mm 2 in VEGF-C-treated aged mice versus 0.26 ± 0.07 mm 2 in vehicle-treated aged mice; P < 0.0001), and decreased percentage of matrix metallopeptidase 13-positive staining area within total synovial area in 22-month-old VEGF-C-treated mice versus 22-month-old vehicle-treated mice (mean ± SD decrease 7 ± 2% versus 4 ± 1%; P = 0.0004).Conclusion. SLS function is reduced in the knee joints of aged mice due to decreased VEGF-C/VEGFR-3 signaling. VEGF-C treatment attenuates OA joint damage and improves synovial lymphatic drainage in aged mice. The SLS and VEGF-C/VEGFR-3 signaling represent novel physiopathologic mechanisms that could potentially be used as therapeutic targets for age-related OA.

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“…Interestingly, it has been shown that the uptake of apoptotic cells by murine alveolar macrophages and human monocyte-derived macrophages is inhibited by Vegf depletion, while Vegf overexpression significantly enhances apoptotic cell uptake by alveolar macrophages in vivo, indicating a positive regulatory role for Vegf in macrophage endocytosis and clearance of apoptotic cells [44]. Furthermore, Vegf-C/Vegfr-3 signaling increases the macrophage efferocytosis of apoptotic neutrophils via the upregulation of macrophage integrin αv [63], further indicating a role for Vegf in regulating macrophage phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

MiR-23a Regulates Skin Langerhans Cell Phagocytosis and Inflammation-Induced Langerhans Cell Repopulation

Wang,

Parajuli,

Wang

et al. 2023

Biology

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Langerhans cells (LCs) are skin-resident macrophage that act similarly to dendritic cells for controlling adaptive immunity and immune tolerance in the skin, and they are key players in the development of numerous skin diseases. While TGF-β and related downstream signaling pathways are known to control numerous aspects of LC biology, little is known about the epigenetic signals that coordinate cell signaling during LC ontogeny, maintenance, and function. Our previous studies in a total miRNA deletion mouse model showed that miRNAs are critically involved in embryonic LC development and postnatal LC homeostasis; however, the specific miRNA(s) that regulate LCs remain unknown. miR-23a is the first member of the miR-23a-27a-24-2 cluster, a direct downstream target of PU.1 and TGF-b, which regulate the determination of myeloid versus lymphoid fates. Therefore, we used a myeloid-specific miR-23a deletion mouse model to explore whether and how miR-23a affects LC ontogeny and function in the skin. We observed the indispensable role of miR-23a in LC antigen uptake and inflammation-induced LC epidermal repopulation; however, embryonic LC development and postnatal homeostasis were not affected by cells lacking miR23a. Our results suggest that miR-23a controls LC phagocytosis by targeting molecules that regulate efferocytosis and endocytosis, whereas miR-23a promotes homeostasis in bone marrow-derived LCs that repopulate the skin after inflammatory insult by targeting Fas and Bcl-2 family proapoptotic molecules. Collectively, the context-dependent regulatory role of miR-23a in LCs represents an extra-epigenetic layer that incorporates TGF-b- and PU.1-mediated regulation during steady-state and inflammation-induced repopulation.

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VEGF-C/VEGFR-3 signalling in macrophages ameliorates acute lung injury

Cited by 22 publications

References 38 publications

Macrophage Sprouty4 deficiency diminishes sepsis-induced acute lung injury in mice

Macrophage Sprouty4 deficiency diminishes sepsis-induced acute lung injury in mice

Targeting Synovial Lymphatic Function as a Novel Therapeutic Intervention for Age‐Related Osteoarthritis in Mice

MiR-23a Regulates Skin Langerhans Cell Phagocytosis and Inflammation-Induced Langerhans Cell Repopulation

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