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

Abstract

BackgroundSuccessful recovery from acute lung injury requires inhibition of neutrophil influx and clearance of apoptotic neutrophils. However, the mechanisms underlying recovery remain unclear. We investigated the ameliorative effects of vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 (VEGFR-3) signalling in macrophages in lipopolysaccharide (LPS)-induced lung injury.MethodsLPS was intranasally injected into wild-type and transgenic mice. Gain and loss of VEGF-C/VEGFR-3 signalling function experiments employed adenovirus-mediated intranasal delivery of VEGF-C (Ad-VEGF-C vector) and soluble VEGFR-3 (sVEGFR-3) or anti-VEGFR-3 blocking antibodies and mice with a deletion of VEGFR-3 in myeloid cells.ResultsThe early phase of lung injury was significantly alleviated by the overexpression of VEGF-C with increased levels of bronchoalveolar lavage (BAL) fluid interleukin-10 (IL-10), but worsened in the later phase by VEGFR-3 inhibition upon administration of Ad-sVEGFR-3 vector. Injection of anti-VEGFR-3 antibodies to mice in the resolution phase inhibited recovery from lung injury. The VEGFR-3-deleted mice had a shorter survival time than littermates and more severe lung injury in the resolution phase. Alveolar macrophages in the resolution phase digested most of the extrinsic apoptotic neutrophils and VEGF-C/VEGFR-3 signalling increased efferocytosis via upregulation of integrin αv in the macrophages. We also found that incubation with BAL fluid from acute respiratory distress syndrome (ARDS) patients, but not from controls, decreased VEGFR-3 expression and the efficiency of IL-10 expression and efferocytosis in human monocyte-derived macrophages.ConclusionsVEGF-C/VEGFR-3 signalling in macrophages ameliorates experimental lung injury. This mechanism may also provide an explanation for ARDS resolution.

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

“…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 ].…”

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

“…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.…”

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

“…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.…”