Project description:Enhanced osteoclast-mediated bone erosion is a prominent hallmark of rheumatoid arthritis. Emerging evidence suggests that this process is facilitated by metabolic dysregulation of osteoclasts. The mitochondrial enzyme aconitate decarboxylase 1 (Acod1, also known as immune responsive gene 1 [Irg1]) serves as a mediator between the metabolic condition and the functional state of different types of cells. Acod1-deficient mice are characterized by enhanced osteoclast differentiation and bone erosion in an inflammatory arthritis model, while therapeutic treatment with the itaconate-derivative 4-octyl-itaconate (4-OI) alleviates the disease phenotype in experimental arthritis. To ascertain the influence of the Acod1-itaconate axis on the genomic transcriptional network of osteoclasts, we performed a whole transcriptome RNA sequencing analysis with fully differentiated osteoclasts from WT and Acod1-deficient mice that were cultured in the presence or absence of 4-OI.
Project description:ACOD1 is the enzyme repurposing cisaconitate from the tricarboxylic acid (TCA) cycle in the mitochondria to produce itaconate, a metabolite with anti-inflammatory and tolerogenic functions. In particular, itaconate accumulation in macrophages is known to oppose pro-inflammatory cytokine production mainly by inhibiting succinate dehydrogenase activity, activating the NRF2 and ATF3driven responses and inhibiting NLRP3. Itaconate biosynthesis was found to be induced in the liver of mice exposed to ischemia reperfusion (I/R) stress and to oppose the resulting tissue injury by sustaining hepatoprotective antioxidant programs. Whether ACOD1 plays a role in the homeostatic response of liver to different noninfectious injuring conditions remains largely unexplored. This study investigates the contribution of itaconate biosynthesis in the response of liver to dietary lipid overload and in the development of associated nonalcoholic fatty liver disease.
Project description:TPL2 (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates cytokine levels and activation states of microglia. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNAseq analysis indicates protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity promotes multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.
Project description:Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.
Project description:The Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Here, we explore the role of endogenous ACOD1-itaconate pathway in the activation of BMDM after imiquimod treatment.
Project description:Microglial activation represents a hallmark of inflammatory retinal diseases like diabetic retinopathy. Anti-inflammatory and especially microglia modulating approaches have been proposed as therapies for these diseases. In this study, clodronate-coated liposomes were intravitreally injected to investigate the effects of increased microglial activation on vasoregression in a model of retinal degeneration. Clodronate-coated liposomes, injected twice over a period of 5 weeks to study the effects of long term clodronate treatment on microglial activation, vasoregression (acellular capillary formation and pericyte loss) and to identify the pathways mediating the observed effects.