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Institut für Neuropathologie

Metabolism and Inflammation Research Group (Head: O. Groß)

Inflammation is a complex response to infection, irritants, or tissue damage that is orchestrated by the innate immune system and its constituent cells and signalling pathways. Coordinated responses of immune cells and tissue-resident cells eventually re-establish homeostasis after inflammation. Failure of these systems can result in persistent infection or inflammatory diseases, with significant morbidity and mortality. Sterile, endogenous danger signals that are frequently by-products of deregulated metabolism are key drivers of chronic, tissue-destructive inflammation. Furthermore, beyond fulfilling the bioenergetic and biosynthetic demands of mobile immune cells, cellular metabolic pathways also control the fate and function of immune cells. On the organismal level, dietary and microbial metabolites are emerging as important regulators of immunity, inflammation, and homeostasis.

Inflammasomes are key players at the interface between metabolism and immunity. These supramolecular protein complex in innate immune cells stringently regulate the bioactivity of potent pro-inflammatory cytokines of the interleukin-1 family. Inflammasomes drive pathological inflammation in numerous diseases of the central nervous system and beyond, including Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease, but also type 2 diabetes, metabolic syndrome, non-alcoholic steatohepatitis, atherosclerosis, gout, and ischemia-reperfusion injury. Chronic, inflammasome-dependent inflammation can also promote cancer development. Consistent with its implication in diseases of aging and dietary excess, reported triggers of the inflammasome include signals of nutrient excess or metabolic stress, such as monosodium urate, calcium oxalate and cholesterol crystals, saturated fatty acids, and dysregulation of glycolysis or the electron transport chain. Despite over a decade of research and overwhelming disease relevance, the precise mechanisms of inflammasome activation is unknown.

We study inflammasome biology on the molecular, cellular and organismal level with the goal to identify new rational targets to control its activity in inflammatory diseases without interfering with the protective function of other parts of the immune system.

Personalia

Prof. Dr. Olaf GroßPrinciple Investigator+49 761 270 51060
Dr. Oliver GorkaPostdoc+49 761 270 62880
Dr. Anna KostinaPostdoc+49 761 270 63880
Monique HavermansPhD Student+49 761 270 63880
Emilia NeuwirthPhD Student+49 761 270 63880
Benedikt SallerPhD Student+49 761 270 62880
Svenja WöhrlePhD Student+49 761 270 62880
Timo KleindienstM.Sc. Biology+49 761 270 62880

Research Topic

Mechanisms of imidazoquinole-mediated Inflammasome activation

Imiquimod acts as a TLR7 ligand and has been licenced for treatment of viral infections and melanoma. Additionally, Imiquimod activates the NLRP3 inflammasome in myeloid cells and has the capacity to trigger apoptosis in tumour cells. We studied the mechanisms by which Imiquimod and other imidazoquinolines activate the inflammasome and found a K+ efflux-independent mode of action that involves the quinone oxidoreductases NQO2 and mitochondrial Complex I. Here, Imiquimod induces the production of reactive oxygen species (ROS) and leads to thiol oxidation which in turn activates NLRP3 via NEK7, a NIMA-related serine/threonine kinase. Our studies demonstrated a novel K+ efflux-independent mechanism for NLRP3 inflammasome activation and suggested clinically relevant targets of Imiquimod (Groß CJ et al. 2016, Immunity).

Figure: Crystal structure of NQO2 in complex with imiquimod. Surface representation of the active site of NQO2 in complex with imiquimod (Groß CJ et al. 2016, Immunity).

Figure: Respiration (OCR) of bone-marrow derived marcophages stimulated with different imidazoquinolines, followed by CCCP and antimycin A (Groß CJ et al. 2016, Immunity).

Principle Investigator

Prof. Dr. Olaf Groß

University Clinic Freiburg

Institute of Neuropathologie
Breisacher Straße 64
79106 Freiburg

Tel: +49 761 270 51060