The hyaluronic acid-rich node and duct system is a structure organized for innate immunity and mediates the local inflammation

Abstract

The Hyaluronic Acid-rich Node and Duct System (HAR-NDS or NDS), Primo Vascular System (PVS) or Bonghan System (BHS), is thought to be a third circulatory system independent of the blood and lymphatic systems and a structure of connected nodes and ducts. Although it seems to be part of the immune system as it is enriched with cells of innate immunity, little is known about its immunological roles. We performed cellular profiling and secretome analysis of NDS in a steady state and under TLR2- or TLR4-mediated local inflammation, and found that the NDS is pre-dominantly enriched with the myeloid cells, selectively attracts the inflammatory macrophages and neutrophils, has a flexible structure just like the lymph node, and is structured with the fibroblastic reticular cells and reticular network. NDS dominantly harbored the myeloid cells in both steady and activated status, and secreted various types of inflammatory cytokines by proinflammatory stimuli. These results suggest that NDS is the lymphoid structure for the innate immunity and plays an intermediary role in the innate immune cell-mediated local inflammation.

Potential Mechanisms of Interior Lymphatic Vessel Primo Vessels in Tissue Repair

“…One of the more elegant mechanistic/ functional studies in the PVS literature was performed by Choi and colleagues 40 . Their group performed cellular profiling and secretome analysis of external subtype PVs and PNs.…”

“…PV samples were harvested from the peritoneal cavity lateral wall, intestine, or liver and analyzed under normal conditions and locally mediated inflammation induced by lipopolysaccharide (LPS) or zymosan. They found that PNs primarily harbored myeloid cells (TER119 + red blood cells (RBCs), Gr-1 High neutrophils, and F4/80 Low macrophages) in both normal and LPS-activated states 40 . With proinflammatory stimuli, various types of inflammatory cytokines and chemokines were secreted by these cells, and simultaneously, the volume of PNs expanded with increasing numbers of neutrophils and macrophages 40 .…”

“…They found that PNs primarily harbored myeloid cells (TER119 + red blood cells (RBCs), Gr-1 High neutrophils, and F4/80 Low macrophages) in both normal and LPS-activated states 40 . With proinflammatory stimuli, various types of inflammatory cytokines and chemokines were secreted by these cells, and simultaneously, the volume of PNs expanded with increasing numbers of neutrophils and macrophages 40 . The results suggest that local inflammation induces migration and accumulation of macrophages and neutrophils into PNs, where inflammatory cytokines and chemokines are amplified, enhancing signaling and alerting the systemic immune system to the presence of an inflammatory site 40 .…”

“…With proinflammatory stimuli, various types of inflammatory cytokines and chemokines were secreted by these cells, and simultaneously, the volume of PNs expanded with increasing numbers of neutrophils and macrophages 40 . The results suggest that local inflammation induces migration and accumulation of macrophages and neutrophils into PNs, where inflammatory cytokines and chemokines are amplified, enhancing signaling and alerting the systemic immune system to the presence of an inflammatory site 40 . Apparently, exterior PVs and PNs in mice serve as a component of the lymphoid system for innate immunity signaling with an intermediary role in cell-mediated local inflammation.…”

“…However, their immune role in aging mice (>7 weeks old) is not clear since exterior subtype PVs and PNs degenerate into thinner thread-like structures with fewer PNs 40 . Choi's group compared the same age wild type C57BL/6 mice with immunodeficient C57BL/6 mice lacking in recombination-activating genes 1 (RAG1 − / − ) to test the hypothesis that immunodeficient mice as they aged would retain their PV and PN morphology since the knockout mice have an undeveloped lymphoid system with no mature B and T lymphocytes 40 . Temporal repeated comparative measurements of PN diameters demonstrated that PNs in 8-week-old RAG1 − / − mice were significantly larger than in control mice, and PNs of immunedeficient mice at 10 weeks of age remained prominent and easily visualized 40 .…”