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Critical role of the CD40-CD40 ligand pathway in governing mucosal inflammation-driven angiogenesis in inflammatory bowel disease
  1. Silvio Danese (sdanese{at}hotmail.com)
  1. Istituto Clinico Humanitas, Italy
    1. Franco Scaldaferri
    1. Università Cattolica, Italy
      1. Stefania Vetrano
      1. Istituto Clinico Humanitas, Italy
        1. Tommaso Stefanelli
        1. Istituto Clinico Humanitas, Italy
          1. Cristina Graziani
          1. Università Cattolica, Italy
            1. Alessandro Repici
            1. Istituto Clinico Humanitas, Italy
              1. Riccardo Ricci
              1. Università Cattolica, Italy
                1. Alessandro Sgambato
                1. Università Cattolica, Italy
                  1. Giuseppe Straface
                  1. Università Cattolica, Italy
                    1. Alberto Malesci
                    1. Istituto Clinico Humanitas, Italy
                      1. Claudio Fiocchi
                      1. Cleveland Clinic, United States
                        1. Sergio Rutella
                        1. Università Cattolica, Italy

                          Abstract

                          Background and aims: Angiogenesis is a novel component in inflammatory bowel disease (IBD) pathogenesis. We have previously shown that immune-nonimmune interactions through the CD40-CD40 ligand (CD40L) pathway might sustain gut inflammation, although their effect in governing inflammation-driven angiogenesis is unknown. The present study evaluated the role of the CD40-CD40L interaction in the promotion of immune-mediated angiogenesis in IBD.

                          Methods: Human nonimmune cells of colonic origin, namely, human intestinal fibroblasts (HIF) and human intestinal microvascular endothelial cells (HIMEC), were activated with either soluble CD40 ligand (sCD40L), or CD40+ D1.1 cells or CD40L-activated lamina propria T cells (LPT) before measuring pro-angiogenic cytokine release. Blocking antibodies to either CD40 or CD40L were used to disrupt the CD40-CD40L interaction. The DSS model of experimental colitis in CD40 and CD40L knock-out mice was established to assess whether the CD40-CD40L pathway was implicated in controlling inflammation-driven angiogenesis in vivo.

                          Results: Engagement of CD40 on HIF promoted VEGF, IL-8 and HGF release. LPT cells were potent inducers of pro-angiogenic cytokine secretion by HIF. Supernatants from sCD40L-activated HIF induced migration of HIMEC and tubule formation both of which were inhibited by blocking antibodies to either VEGF or IL-8 or HGF. Both CD40- and CD40L-deficient mice were protected from DSS-induced colitis and displayed a significant impairment of gut inflammation-driven angiogenesis, as assessed by microvascular density.

                          Conclusions: The CD40-CD40L pathway appears to be crucially involved in regulating inflammation-driven angiogenesis, suggesting that strategies aimed at blocking CD40L-CD40 interactions might be beneficial in acute and chronic intestinal injury.

                          • CD40
                          • IBD
                          • angiogenesis
                          • endothelium

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