Vascular Microarchitecture of Murine Colitis‐Associated Lymphoid Angiogenesis

Abstract

In permissive tissues, such as the gut and synovium, chronic inflammation can result in the ectopic development of anatomic structures that resemble lymph nodes. These inflammation-induced structures, termed lymphoid neogenesis or tertiary lymphoid organs, may reflect differential stromal responsiveness to the process of lymphoid neogenesis. To investigate the structural reorganization of the microcirculation involved in colonic lymphoid neogenesis, we studied a murine model of dextran sodium sulfate (DSS)-induced colitis. Standard 2-dimensional histology demonstrated both submucosal and intramucosal lymphoid structures in DSSinduced colitis. A spatial frequency analysis of serial histologic sections suggested that most intramucosal lymphoid aggregates developed de novo. Intravital microscopy of intravascular tracers confirmed that the developing intramucosal aggregates were supplied by capillaries arising from the quasi-polygonal mucosal plexus. Confocal optical sections and whole mount morphometry demonstrated capillary networks (185 AE 46 lm diameter) involving six to ten capillaries with a luminal diameter of 6.8 AE 1.1 lm. Microdissection and angiogenesis PCR array analysis demonstrated enhanced expression of multiple angiogenic genes including CCL2, CXCL2, CXCL5, Il-1b, MMP9, and TNF within the mucosal plexus. Intravital microscopy of tracer particle flow velocities demonstrated a marked decrease in flow velocity from 808 AE 901 lm/sec within the feeding mucosal plexus to 491 AE 155 lm/sec within the capillary structures. We conclude that the development of ectopic lymphoid tissue requires significant structural remodeling of the stromal microcirculation. A feature of permissive tissues may be the capacity for lymphoid angiogenesis. Anat Rec, 292:621-632, 2009

CXCL5 is required for angiogenesis, but not structural adaptation after small bowel resection

“…The expression of this chemokine has been shown to be elevated within the gut mucosa under conditions of angiogenesis associated with intestinal inflammation [26]. We have not identified gross evidence for inflammation in the intestine of our animals undergoing SBR.…”

Ectopic lymphoid tissue formation in the lungs of mice infected with Chlamydia pneumoniae is associated with epithelial macrophage inflammatory protein-2/CXCL2 expression

“…Various signals are necessary for ectopic lymphoid tissue formation in inflammatory settings [30], but the initiating mechanisms are not understood completely. MIP‐2/CXCL2 is important for recruitment of neutrophils and lymphocytes by gut epithelial cells [18]; in lymphocyte trafficking during autoimmune responses [16]; and for recruitment of lymphocytes to peripheral organs in graft‐ versus ‐host disease [17]; and has been implicated in the neo‐angiogenesis associated with ectopic lymphoid tissue formation [19]. The finding that Cp infection induces lung epithelial cell expression of MIP‐2/CXCL2 and secretion both in vivo and in vitro suggests a mechanism by which both neutrophilia and lymphocytosis may develop and formation of ectopic lymphocyte tissue may be initiated by Cp infection of lung epithelial cells in vivo .…”

“…We investigated a link between cytokine production by Cp‐infected lung epithelial cells and inflammation. The chemokine macrophage inflammatory protein (MIP)‐2/CXCL2 recruits both neutrophils and lymphocytes [16–18] and is associated with ectopic lymphoid tissue formation [19]. It has been reported that epithelial cell secretion of MIP‐2/CXCL2 recruits both lymphocytes and neutrophils to the gut [18].…”