During innate immune responses, proteostasis is severely challenged by inflammatory damage through radicals or other tissue damaging molecules. This is particularly important for myeloid cells of the central nervous system (CNS) as their function is closely connected with phagocytosis, radical production and profound changes of their phenotype during activation. The ubiquitin proteasome system (UPS) plays a pivotal role in this proteostasis network. Impairment of proteasome function cause the induction of type I interferons, which drive a vicious cycle of protein damage by radical production and dysfunction in clearance of these damaged proteins in (auto)inflammation. Nevertheless, our understanding of the biological processes that control the biogenesis, folding, trafficking and degradation of proteins in microglia and brain macrophages is very limited. In this project, we investigate the role of the UPS in myeloid cell function in the CNS. In particular, we shall perform transcriptional profiling, posttranscriptional regulation and protein expression studies of UPS components in parenchymal microglia, perivascular macrophages and blood-borne monocytes. The different myeloid cell types will be examined in vitro, in organotypic slice cultures and in vivo under physiological conditions, as well as in response to systemic inflammation (lipopolysaccharide/polyI:C) and neurodegeneration (polyQ peptides; Huntington’s disease transgenic mice). Functional assays will be performed using proteasome inhibitors and immunoproteasome-deficient mice. Human induced pluripotent stem cells (iPSCs) from patients with proteasome mutations and healthy donors will be models examined in the long run. These studies will also reveal whether proteotoxic stress in myeloid cells of the brain will induce type I interferons.