Lymphatic Vessel Memory Stimulated by Recurrent Inflammation

Abstract

Inflammation stimulates new lymphatic vessel growth (inflammatory lymphangiogenesis). One key question is how recurrent inflammation, a common clinical condition, regulates lymphatic vessel remodeling. We show here that recurrent inflammation accelerated the development a functional lymphatic vessel network. This observation suggests a novel program of lymphangiogenesis and identifies a property of lymphatic vessel memory in response to recurrent inflammation. A brief episode of initial inflammation regressed lymphatic vessels, and a significant increase in CD11b(+) macrophages were associated with the development of lymphatic vessel memory. These vessels had major differences in the structure and the spatial distribution of specialized lymphatic vessel features. Surprisingly, we found that the lymphatic vessel memory response did not depend on the vascular endothelial growth factor C or A pathway, indicating that different molecular pathways regulate inflammatory lymphangiogenesis and lymphatic vessel memory. These findings uncover a priming mechanism to facilitate a rapid lymphatic vessel memory response: a potential important component of peripheral host defense.

Inflammation-associated lymphangiogenesis: a double-edged sword?

“…Upon recurrent inflammation, lymphatic vessel memory provokes an accelerated expansion of structurally distinct but functioning lymphatic vessels. Of note, this category of lymphangiogenesis depends on neither the VEGF-C/VEGFR-3 axis nor the VEGF-A/VEGF-R2 axis (50). Further study is necessary to elucidate how this novel mechanism contributes to IAL.…”

“…Recently, Kelley et al proposed the concept of lymphatic vessel memory (50). Upon recurrent inflammation, lymphatic vessel memory provokes an accelerated expansion of structurally distinct but functioning lymphatic vessels.…”

Lymphatic vessels and tertiary lymphoid organs

“…Interestingly, there is downregulation of other genes, including Vegfr3 and Prox1. Extension of these studies to LVs in TLOs may reveal differences due to the chronic nature of stimulation, and data from a mouse corneal model of recurrent inflammation suggest that this is the case (78). The authors suggest that, in chronic inflammation, LVs retain memory in their accelerated development of a network of functional LVs (78).…”

“…Extension of these studies to LVs in TLOs may reveal differences due to the chronic nature of stimulation, and data from a mouse corneal model of recurrent inflammation suggest that this is the case (78). The authors suggest that, in chronic inflammation, LVs retain memory in their accelerated development of a network of functional LVs (78). The ability to isolate LVs on the basis of their antigen expression (77) or transgene induced fluorescence (79) will allow their molecular analysis and comparison to vessels from resting LNs, activated LNs, and TLOs.…”

Lymphangiogenesis and Inflammation—Looking for the “Missing Pieces” of the Puzzle

“…and CD8 ? T cells may play a role in recurrent pterygium lymphangiogenesis most probably due to lymphatic vessels' memory stimulated by recurrent inflammation (Kelley et al 2013). …”