PT Unknown AU Bremer, L TI Functional characterization of NLRC3 PY 2014 PU Christian-Albrechts-Universität zu Kiel WP https://macau.uni-kiel.de/receive/diss_mods_00014558 LA en DE NLRC3; NLR; Inflammation; DSS; colitis; Entzündung; Kolitis AB The innate immune system relies on several pattern recognition receptors (PRRs) to identify pathogen associated molecular patterns (PAMPs). One of the most prominent non-clonal, germline encoded but yet not fully characterized PRR group are the NOD-like receptors (NLRs). Here I aim to characterize a hitherto rarely described member of the NLRs named NOD-like receptor CARD domain containing 3 (NLRC3). Recent studies indicated, that NLRC3 is a cytosolic receptor which negatively regulates T cell function. This thesis utilizes several experimental approaches to access the cellular localization of NLRC3, its functional interactions, and role in inflamed tissue. Microscopical studies showed, that NLRC3 is localized in the cytoplasm. Analysis of different organs indicated, that NLRC3 transcript level are elevated in immune relevant tissues, but not in the intestinal tract. A Y2H screen indicated a potential interaction with the mitochondrial protein IMMT/Mitofilin. Although a direct interaction remained elusive, NLRC was detected in close spatial proximity of mitochondria via immunefluorescence and identified in mitochondrial lysates. NLRC3 was found to interfere with NFB signaling in a dose dependent manner. Dual luciferase assays were performed revealing connections to TRAF6 and ERSE. NLRC3 seems to negatively regulate the TRAF6 mediated NFB response. In combination with a potent stressor, such as tunicamycin elevates NLRC3 the ERSE promoter activity. This reaction connects NLRC3 to cellular mechanisms of the unfolded protein response, and subsequently to mitochondrial stress reactions. NLRC3 was found to be downregulated in biopsies of WG patients. During this thesis Nlrc3+/+ and Nlrc3-/- mice were bred and utilized in several experiments. Cytokine level in bone marrow derived macrophages varied between Nlrc3+/+ and Nlrc3-/- in response to LPS stimulation. A DSS induced colitis was conducted and revealed, that NLRC3 seems to be beneficial for survival and disease severity. These experiments significantly enlarged the knowledge about NLRC3, pointing at the protective role of NLRC3 during cellular stress response and inflammation. NLRC3 is an important regulator in immune modulation. PI Kiel ER