The role of CCL17 and CCL17-expressing dendritic cells in intestinal Inflammation

• Applicant: Professorin Dr. Anne Krug
• Subject Area: Gastroenterology ; Immunology
• Term: from 2007 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 46383290

We could show that the chemokine CCL17 plays a critical role in intestinal inflammation. Mice lacking CCL17 were protected from severe inflammation in murine colitis models. CCL17 amplifies proinflammatory cytokine production by dendritic cells (DCs) in the induction phase and prevents regulatory T cell expansion and maintenance in the effector phase of colitis leading to a dysbalance of T helper (Th)1/Th17 effector T cells and regulatory T cells. In this study, we have unraveled a novel function of CCL17, namely its autocrine/paracrine enhancing effect on cytokine production by DCs in response to Toll-like receptor (TLR) stimulation. The overall aim of the follow up project is now to clarify how CCL17 exerts its proinflammatory effect in the intestine and to establish a basis for CCL17 as a therapeutic target in inflammatory bowel disease (IBD). The first aim is to investigate the influence of CCL17 on DC subset composition in the intestine. We have preliminary evidence that lack of CCL17 leads to accumulation of CD103+ DCs and a reduced frequency of CD103- CD11b+ DCs correlating with expansion of regulatory T cells and protection from colitis. We will therefore characterize in more detail the frequency, phenotype and migratory function of intestinal DC and macrophage subpopulations in CCL17-deficient and CCL17-competent mice in the steady state and during inflammation. Furthermore CCL17-expressing DCs in the intestine will be characterized phenotypically with a panel of DC subset defining markers using the CCL17-eGFP reporter mice and functionally by selective depletion of CCL17-expressing DCs. In addition, their developmental origin in steady state and during inflammation will be investigated by in vivo transfer of defined precursor cells. The second aim is to elucidate the autocrine/paracrine effect of CCL17 on CCR4-expressing DCs leading to enhanced inflammatory cytokine production. The TLR and chemokine receptor signaling pathways may converge at several points. Therefore activation of these signaling pathways by simultaneous triggering of TLRs and CCR4 (by CCL17) will be investigated and the role of specific molecules will be further studied by siRNA knockdown in DCs.The third aim is to explore the role of CCL17 as therapeutic target in a preclinical colitis model and in human inflammatory bowel disease. We plan to neutralize CCL17 using a blocking antibody in murine experimental colitis. Furthermore we will determine the frequency and phenotype of human CCL17-expressing DCs in biopsies of inflamed and non-inflamed colon tissue from IBD patients and normal controls to test the hypothesis that CCL17 expression is a marker for inflammatory DCs in human IBD. Thus, we hope to generate data supporting further study of CCL17 as therapeutic target in IBD.

• DFG Programme: Research Grants
• Participating Person: Dr. Wolfgang Reindl