Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation

Abstract

Oncogenic mutations in PIK3CA, encoding p110α-PI3K, are a common cause of venous and lymphatic malformations. Vessel type–specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C–producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.

Three-dimensional morphologic and molecular atlases of nasal vasculature

“…Furthermore, PROX1 + LECs constituting nasal LVs had low LYVE1 expression but high expression of CCL21, PDPN, MRC1, STAB2 and PTX3 (Fig. 5h), which are involved in immune cell recruitment and transmigration, antigen presentation and immune modulation 13,39,40 . These findings indicate that the morphological and molecular landscapes of the nasal mucosal vasculature are largely conserved between mouse and human.…”

The role of key biomarkers in lymphatic malformation: An updated review

“…Reduced macrophage counts, CCL2 blockade or inhibition of the COX‐2 anti‐inflammatory pathway limited the development of lymphatic vessels stimulated by PIk3CA H1047R. Therefore, focusing on the interaction between iLECs and macrophages may be a cutting‐edge therapeutic strategy for the treatment of LMs 53 . There have been descriptions of pathways that clarify the relationships between innate and adaptive immunity, but it is still unclear how LMs contribute to inflammation or how they are connected to lymphoid aggregate immunological activity.…”

“…Therefore, focusing on the interaction between iLECs and macrophages may be a cutting-edge therapeutic strategy for the treatment of LMs. 53 There have been descriptions of pathways that clarify the relationships between innate and adaptive immunity, but it is still unclear how LMs contribute to inflammation or how they are connected to lymphoid aggregate immunological activity. Type 1 interferon and plasmacytoid dendritic cells (pDCs) are the major components of this pathway.…”

Lessons of Vascular Specialization From Secondary Lymphoid Organ Lymphatic Endothelial Cells

“…In line with this hypothesis, PTX3 was upregulated in hyperproliferative dermal lymphatic vessels in response to constitutive activation of PI3 (phosphoinositide 3) kinase-signaling. 66 Such PTX3 high LECs expressed monocyte chemoattractant CCL2 and recruited VEGF-C + (vascular endothelial growth factor c) monocytes, 66 although the role of PTX3 in this process is still unknown. In line with these findings, while LN PTX3-LECs do not produce CCL2 under homeostatic conditions, they upregulate this chemokine in response to oxazolone-induced inflammation.…”