Kurzfassung

Maintenance of immune homeostasis in health and disease is linked to the coordinated migration of immune cells and their secretion of pro- and anti-inflammatory mediators. Critical players in inflammation are macrophages (MØ) and dendritic cells (DC). Beyond orchestrating the adaptive immune response, their activation triggers innate immunity, leading to the recruitment of granulocytes and initiation of the inflammatory cascade. Microtubules regulate many cellular functions ranging from cell...Maintenance of immune homeostasis in health and disease is linked to the coordinated migration of immune cells and their secretion of pro- and anti-inflammatory mediators. Critical players in inflammation are macrophages (MØ) and dendritic cells (DC). Beyond orchestrating the adaptive immune response, their activation triggers innate immunity, leading to the recruitment of granulocytes and initiation of the inflammatory cascade. Microtubules regulate many cellular functions ranging from cell motility and signaling to vesicle transport and secretion of soluble mediators. Accumulating evidence suggests that posttranslational modifications (PTM) of tubulin play a crucial role in regulating the functional diversity of microtubules. In fact, an intriguing concept is emerging that the spatially and temporally restricted formation of tubulin PTM patterns, the tubulin code, creates distinct microtubule identities and thus coordinates cellular functions. Although tubulin PTM control vital features such as cell migration and signaling, little is known concerning the role of microtubules and their PTM in regulating immune cells, in particular of the myeloid lineage. The Janke team recently identified mammalian enzymes catalyzing PTM of tubulin and together we have established a unique collection of loxP-flanked mice for the generation of cell type-specific knockouts of these enzymes. This enables us for the first time, to investigate tubulin PTM and their functional implications in vivo.
Our preparatory experiments indicate that mice deficient (-/-) for the tubulin-modifying glycylase TTLL3 display an augmented susceptibility to chemically induced colitis. This phenotype is associated with an increased migratory capacity of TTLL3-/- granulocytes and elevated production of pro-inflammatory cytokines by TTLL3-/- myeloid cells. Furthermore, we discovered that TTLL4-/- myeloid cells secrete higher levels of pro-inflammatory cytokines as well as anti-inflammatory IL-10. Expression analysis of all known tubulin-modifying enzymes across different myeloid cell populations revealed that TTLL3 is preferentially expressed by granulocytes and DC, the tubulin tyrosine ligase TTL by MØ and the glutamylase TTLL4 by DC, respectively. Notably, the remaining tubulin-modifying enzymes are not expressed, strongly suggesting that TTL, TTLL3 and TTLL4 play critical and non-redundant functions in distinct myeloid cells. The overall aim of this research proposal is to use conditional TTLL3 and TTLL4 knockout mice to decipher the role of these tubulin-modifying enzymes to govern in particular DC function in vivo, in the steady state and during inflammation. Specifically, we will focus our analysis on mouse models of selected immune-mediated inflammatory diseases (IMID), including colitis, contact dermatitis and psoriasis. Beyond increased understanding of the molecular control of DC, this project may reveal new targets to design improved therapeutic strategies to treat human IMID.» weiterlesen» einklappen