Role of the CCL17/CCL22-CCR4-axis in the barrier organs skin and gut

Abstract

The chemokines C-C motif chemokine ligand 17 (CCL17) and C-C motif chemokine ligand 22 (CCL22) are ligands of the C-C motif chemokine receptor 4 (CCR4). They are mainly secreted by dendritic cells and macrophages to recruit CCR4-expressing T cells. Although both chemokines bind the same receptor, they possess different affinities to CCR4, with CCL22 being the dominant ligand. Moreover, they exert different immune functions. While CCL17 expression often occurs during inflammation, CCL22 is rather involved in regulatory processes. Both chemokines are known to be involved in inflammatory diseases of barrier organs. <br /> In this PhD thesis, the role of CCL17, CCL22 and their receptor CCR4 in development of diseases affecting the barrier organs skin and gastrointestinal tract was investigated. To study this, pharmacological inhibition of the chemokines or mice deficient for different components of the CCL17/CCL22-CCR4-axis were used in mouse models for allergic contact dermatitis (ACD), atopic dermatitis (AD) and inflammatory bowel diseases (IBD). <br /> First, as we observed that CCL17- or CCL22-deficiency reduced allergic reactions in contact hypersensitivity (CHS), the mouse model for ACD, a CCL17-specific RNA aptamer was used in CHS experiments to further assess its therapeutic efficacy. Testing of different injection time-points revealed that the duration of action was likely in the range of 12 h–24 h, and that the CCL17-specific aptamer still displayed suppressive functions when applied at a later time-point, though the suppressive capacity did not persist for a second allergen challenge. <br /> Additionally, to test the role of CCL22 in CHS and to investigate CCL22 as a potential target for ACD therapy, CCL22-specific DNA aptamers, newly generated by Anna Jonczyk, were tested functionally <em>in vitro</em> and <em>in vivo</em>. The most promising aptamer AJ102.29m was applied intraperitoneally and topically during a CHS experiment. Both application methods could effectively suppress ear swelling during CHS and decrease T cell migration into the ears. These data show that topical application of an aptamer in a cream has the potential for development of a non-invasive local ACD treatment. <br /> The last part of the thesis covers the analysis of the CCL17/CCL22-CCR4-axis in development of IBD by employing the dextran sodium sulfate (DSS)-induced colitis model. While similar colitis symptoms could be observed for CCL17-deficient and wild type mice, CCL22-deficient and to a lesser degree CCL17- and CCL22-double deficient mice, as well as CCR4-deficient mice were protected from severe colitis induced symptoms. Their mesenteric lymph nodes contained significantly more T cells and the mice displayed less severe weight loss, colon-shortening and immune cell infiltration into the colon. The results confirmed the importance of CCL22 in the development of colitis and hint towards the existence of a fourth player in the CCL17/CCL22-CCR4-axis.