Role of CD11b+ Macrophages in Intraperitoneal Lipopolysaccharide-Induced Aberrant Lymphangiogenesis and Lymphatic Function in the Diaphragm

Abstract

Lymphatic vessels in the diaphragm are essential for draining peritoneal fluid, but little is known about their pathological changes during inflammation. Here we characterized diaphragmatic lymphatic vessels in a peritonitis model generated by daily i.p. administration of lipopolysaccharide (LPS) in mice. Intraperitoneal LPS increased lymphatic density, branching, sprouts, connections, and network formation in the diaphragm in time-and dose-dependent manners. These changes were reversible on discontinuation of LPS administration. The LPS-induced lymphatic density and remodeling occur mainly through proliferation of lymphatic endothelial cells. CD11b؉ macrophages were massively accumulated and closely associated with the lymphatic vessels changed by i.p. LPS. Both RT-PCR assays and experiments with vascular endothelial growth factor-C/D blockade and macrophage-depletion indicated that the CD11b ؉ macrophage-derived lymphangiogenic factors vascular endothelial growth factor-C/D could be major mediators of LPS-induced lymphangiogenesis and lymphatic remodeling through paracrine activity. Functional assays with India ink and fluorescein isothiocyanate-microspheres indicated that impaired peritoneal fluid drainage in diaphragm of LPS-induced peritonitis mice was due to inflammatory fibrosis and massive attachment of CD11b ؉ macrophages on the peritoneal side of the diaphragmatic lymphatic vessels. These findings reveal that CD11b ؉ macrophages play an important role in i.p. LPS-induced aberrant lymphangiogenesis and lymphatic dysfunction in the diaphragm.

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

“…3A). TNF-␣ is induced by LPS, which also significantly affects lymphatic function (5,26). To assess whether the relative levels of miR-9 are increased in vivo in the lymphatic tissues under systemic inflammatory conditions as induced by LPS, we determined the expression of miR-9 in mesenteric lymphatic vessels isolated from normal rats and rats treated intraperitoneally with LPS for 24 h. Figure 3B shows that LPS causes a significant induction in the relative levels of IL-1␤, IL-6, MCP-1, c-fos, and MIP-2 in mesenteric lymphatic vessels, suggesting widespread inflammatory signaling in the mesentery of LPS-injected rats.…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…Both the increase of interstitial pressure and flow, as well as the change in cytokines and inflammatory mediators, stand to influence this drainage, yet the latter is only beginning to be explored [38,39]. Transmural flow itself can activate the lymphatic endothelium, increasing fluid and solute permeability and uptake as well as upregulating adhesion molecules required for immune cell transmigration [40].…”

Cellular phenotypes and spatio‐temporal patterns of lymphatic vessel development in embryonic mouse hearts

“…However, their lineage tracing studies definitely excluded cells of myeloid lineage (Lyve-1-expressing macrophages) as a source of lymphatic endothelial progenitor during embryonic development and in tumor environment by demonstrating that macrophages bearing the Lyve-1 antigen were Prox-1-negative (Gordon et al, 2010). Various authors have reported that macrophages bearing the Lyve-1 antigen may contribute to neolymphangiogenesis during inflammation and tumor environment by producing proangiogenic stimuli, including growth factors: VEGF-A, VEGF-C, and VEGF-D (Schoppmann et al, 2002;Cursiefen et al, 2004;Baluk et al, 2005;Maruyama et al, 2007;Jeon et al, 2008;Kataru et al, 2009;Kim et al, 2009). The results by Gordon et al (2010) indicate that macrophages are not a major source of prolymphagniogenic factors in the skin.…”