Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

Abstract

Inflammation plays a crucial role in the occurrence and development of renal fibrosis, which ultimately results in end-stage renal disease (ESRD). There is new focus on lymphangiogenesis in the field of inflammation. Recent studies have revealed the association between lymphangiogenesis and renal fibrosis, but the source of lymphatic endothelial cells (LECs) is not clear. It has also been reported that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms in other tissues. We hypothesized that there was a close relationship between macrophages and lymphatic endothelial progenitor cells in renal fibrosis. In this study, we demonstrated that lymphangiogenesis occurred in a renal fibrosis model and was positively correlated with the degree of fibrosis and macrophage infiltration. Compared to resting (M0) macrophages and alternatively activated (M2) macrophages, classically activated (M1) macrophages predominantly transdifferentiated into LECs in vivo and in vitro. VEGF-C further increased M1 macrophage polarization and transdifferentiation into LECs by activating VEGFR3. It was suggested that VEGF-C/VEGFR3 pathway activation downregulated macrophage autophagy and subsequently regulated macrophage phenotype. The induction of autophagy in macrophages by rapamycin decreased M1 macrophage polarization and differentiation into LECs. These results suggested that M1 macrophages promoted lymphangiogenesis and contributed to newly formed lymphatic vessels in the renal fibrosis microenvironment, and VEGF-C/VEGFR3 signaling promoted macrophage M1 polarization by suppressing macrophage autophagy and then increased the transdifferentiation of M1 macrophages into LECs.

Cellular and molecular mediators of lymphangiogenesis in inflammatory bowel disease

“…It is demonstrated that VEGFR-3 blockade significantly affects lymphangiogenesis, reducing both area density and lymphatic vessel dimension while significantly increasing inflammatory edema formation and inhibiting disease resolution [ 5 ]. This is consistent with other fairly recent studies in which blockade of VEGFR-3 aggravated IBD and lymphatic vessel enlargement [ 105 ], degradation of VEGFR-3 inhibited lymphagiogenesis [ 106 ], and VEGF-C/VEGFR3-dependent autophagy and polarization triggered lymphangiogenesis [ 107 ]. The systemic delivery of VEGF-C provides significant protection against acute and chronic colitis.…”

Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea

“…Compared with M0 macrophages and M2 macrophages, M1 macrophages can significantly promote lymphangiogenesis by transdifferentiating into lymphatic endothelial cells (LECs). 11 Moreover, TNFα and IL-1β secreted by M1 macrophages can also promote lymphatic endothelial cell proliferation by increasing vascular endothelial growth factor C (VEGF-C) expression in LECs. 12 , 13 During the pathological process of CGR, corneal lymphangiogenesis is the most important mediator of the immune response after transplantation.…”

Mechanism of allergic rhinitis treated by Centipeda minima from different geographic areas

“… 2012 ; Zhang et al. 2021 ). Our analysis identified 117 proteins that may be involved in the generation of synergistic anti-inflammatory effects and impact the described above 137 inflammation-related pathways.…”