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P039. Adipokines of the mesenteric fat tissue modulate subtype and function of resident macrophages

L. Kredel, A. Batra, D. Lissner, A. Kühl, M. Zeitz, B. Siegmund

Charité Berlin, Berlin, Germany

Aim: In the hypertrophic mesenteric fat tissue of patients with Crohn's disease a macrophage invasion can be found and adipokine levels are elevated compared to healthy tissue. The interaction between adipokines and macrophage subpopulations has not been studied yet. Thus the aim of the present study was to evaluate the in-situ-phenotype of macrophages in human mesenterial adipose tissue and the effect of adipokines on macrophage polarization and functions in-vitro.

Materials and Methods: M1- and M2-macrophages in the mesenteric fat tissue of patients with Crohn's disease (CD), ulcerative colitis (UC) and colorectal carcinoma (CRC) were analyzed by immunohistochemistry and compared to healthy controls. Peripheral blood monocytes were isolated and polarized into M1- and M2-macrophages. The effect of adiponectin and leptin on the immune phenotype of macrophages was characterized. The influence of adipokines on their chemotatic potency was analyzed using transmigration assays.

Results: The number of CD68+ macrophages in the mesenteric fat tissue of patients with CD in-situ was profoundly increased compared to all other experimental groups included. Our results identified a unique subpopulation of macrophages within the mesenteric fat tissue of CD patients. These could be characterized by a predominant CD163+ and Stabilin1+ expression, suggesting an accumulation of M2-macrophages. In subsequent studies the modulatory effect of leptin and adiponectin, both known to be overexpressed in CD's mesenteric fat tissue, was evaluated. In M1-macrophages TNFα and IL-8 levels were increased following stimulation with leptin, whereas in M2-macrophages this resulted in an enhanced production of their marker cytokines IL-10 and IL-6. Adiponectin exerted similar effects on cytokine production of both subtypes. Furthermore adiponectin stimulation increased the expression of mannose receptor CD206 in M2-macrophages. Remarkably, the response to adipokine stimulation was much stronger in M2-macrophages. Both subpopulations were able to attract CD4+ cells in vitro, however, leptin additionally increased the chemotactic potency of M2-macrophages.

Conclusion: Our data provide strong evidence for a unique M2-macrophage subtype within the mesenteric fat tissue of CD patients, whose function is regulated by the local adipokine milieu.