Session Title: Inflammation
TRANSCRIPTOMIC ANALYSIS REVEALS DISTURBED INFLAMMATORY AND APOPTOTIC RESPONSE IN LIPID-LADEN HUMAN NIEMANN-PICK DISEASE TYPE C MACROPHAGES
K. Leuthaeuser-Jaschinski1, E. Orsó1, H.-H. Klünemann2, G. Schmitz1
Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder mainly due to mutations of the NPC1 gene leading to progressive neurodegeneration and hepatosplenomegaly. Activation of microglia plays a major role in the neurodegenerative processes of NPC. Since microglia and macrophages are derived from a common progenitor, alterations of NPC macrophages may reflect some aspects of microglial overactivation. Therefore we compared the transcriptomic profiles of human NPC1 and control macrophages in an in vitro differentiation and lipid-loading model by microarray analysis. Functional annotation clustering of differentially expressed genes revealed a high number of genes encoding mitochondrial proteins including components of the electron transport chain. In addition, we identified clusters of genes related to lipid and eicosanoid metabolism, apoptosis and programmed cell death, stress and inflammatory response. Differential expression of selected genes was validated by real time-PCR. The differential expression of genes involved in prostaglandin metabolism, higher transcript levels of interleukin-8 and orosomucoid-1 and lower expression of chitinase-3-like protein 1 (CHI3L1) indicate deregulated inflammatory processes concomitant with differential expression of NF-κB and PPARgamma target genes in NPC. Lower expression levels of anti-apoptotic genes, e.g. FAIM and UCHL1, indicate higher susceptibility of NPC1 cells for apoptosis. In conclusion, this first comparative transcriptomic analysis of human NPC1 macrophages sheds new light on the molecular mechanisms how disturbed intracellular cholesterol trafficking might lead to inflammation and cell death with importance for neurodegeneration not only in NPC.