Sialoglycans on lymphatic endothelial cells augment interactions with Siglec‐1 (CD169) of lymph node macrophages

Abstract

Cellular interactions between endothelial cells and macrophages regulate macrophage localization and phenotype, but the mechanisms underlying these interactions are poorly understood. Here we explored the role of sialoglycans on lymphatic endothelial cells (LEC) in interactions with macrophage-expressed Siglec-1 (CD169). Lectin-binding assays and mass spectrometric analyses revealed that LEC from human skin express more sialylated glycans than the corresponding blood endothelial cells. Higher amounts of sialylated and/or sulfated glycans on LEC than BEC were consistently observed in murine skin, lung and lymph nodes. The floor LEC of the subcapsular sinus (SCS) in murine lymph nodes (LN) displayed sialylated glycans at particularly high densities. The sialoglycans of LN LEC were strongly bound by Siglec-1. Such binding plays an important role in the localization of Siglec-1 + LN-SCS macrophages, as their numbers are strongly reduced in mice expressing a Siglec-1 mutant that is defective in sialoglycan binding. The residual Siglec-1 + macrophages are less proliferative and have a more anti-inflammatory phenotype. We propose that the densely clustered, sialylated glycans on the SCS floor LEC are a key component of the macrophage niche, providing anchorage for the Siglec-1 + LN-SCS macrophages.

Immunomodulatory Responses of Subcapsular Sinus Floor Lymphatic Endothelial Cells in Tumor-Draining Lymph Nodes

“…Recently, we transcriptionally characterized LN-resident macrophages and revealed that CLEC-2 is largely absent from MSMs [ 70 ], suggesting the participation of alternative podoplanin receptors in mediating MSM interactions, such as CD44 or the recently identified CD177 [ 71 ] that are more highly expressed in MSMs at steady-state [ 70 ]. In addition, podoplanin might mediate sinusoidal macrophage adhesion to LECs through attached sialoglycans binding to CD169 [ 72 ].…”

Post-COVID syndrome is associated with capillary alterations, macrophage infiltration and distinct transcriptomic signatures in skeletal muscles

“…The mere fact that the number of CD169 + macrophages is increased in mildly altered skeletal muscle tissue is remarkable. CD169 + macrophages are increased in idiopathic inflammatory myopathies ( 54 ), indicating a prominent role in type I Interferon-related immune processes ( 55 ), and recent studies emphasized their highly specific functional programmes and important roles as border-associated cells at blood vessel/parenchymal interfaces ( 56, 57 ). CD169 + macrophages have further been implicated in antiviral defense, being the primary cell infected and able to capture viral particles in the blood and subsequently presenting them to B cells ( 58 ).…”

Lymph node lymphatic endothelial cells as multifaceted gatekeepers in the immune system

“…Sinusoidal LECs are crucial for promoting the differentiation of LN-resident macrophages [61][62][63]. Genetically engineered mice have been especially important for dissecting the roles of key molecules mediating LEC-macrophage interactions: conditional deletion of colony stimulating factor-1 (CSF-1) production by LECs (Prox1 creERT2 Rosa tdTOM Csf1 flox/flox mice) leads to a marked reduction in the number of subcapsular and medullary sinus macrophages compared to wildtype controls, demonstrating the importance of CSF-1 in maintaining the macrophage niche in lymphatic sinuses [61].…”

“…In addition, Rank deficiency in LECs (Rank ΔProx1 mice) during normal embryogenesis as well as during vesicular stomatitis virus infection in adult mice reduces the number of sinus macrophages [62]. Moreover, interactions between sialoglycans, which are highly displayed on SCS floor LECs, and Siglec-1/ CD169 on macrophages, are crucial for regulating macrophage localization, as well as the proinflammatory phenotype of mouse SCS LECs [63]. Thus, the molecular interactions between macrophages and LECs appear to be important for the proper anatomical localization and function of macrophages.…”