Shirong Liu

Publications

• 5.65

  Impact points

  TLR2 is a primary receptor for Alzheimer's amyloid β peptide to trigger neuroinflammatory activation.

  Shirong Liu, Yang Liu, Wenlin Hao, Lisa Wolf, Amanda J Kiliaan, Botond Penke, Claudia E Rübe, Jochen Walter, Michael T Heneka, Tobias Hartmann, Michael D Menger, Klaus Fassbender

  Journal of immunology (Baltimore, Md. : 1950). 12/2011; 188(3):1098-107.

  Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti... [more] Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aβ via phagocytosis. TLRs are associated with Aβ-induced microglial inflammatory activation and Aβ internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aβ (Aβ42). TLR2 deficiency reduced Aβ42-triggered inflammatory activation but enhanced Aβ phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aβ42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aβ42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aβ to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis.
• 9.49

  Impact points

  Myeloid differentiation factor 88-deficient bone marrow cells improve Alzheimer's disease-related symptoms and pathology.

  Wenlin Hao, Yang Liu, Shirong Liu, Silke Walter, Marcus O Grimm, Amanda J Kiliaan, Botond Penke, Tobias Hartmann, Claudia E Rübe, Michael D Menger, Klaus Fassbender

  Brain : a journal of neurology. 01/2011; 134(Pt 1):278-92.

  Alzheimer's disease is characterized by extracellular deposits of amyloid β peptide in the brain. Increasing evidence suggests that amyloid β peptide injures neurons both directly and indirectly by triggering neurotoxic innate immune responses. Myeloid differentiation factor 88 is the key signal... [more] Alzheimer's disease is characterized by extracellular deposits of amyloid β peptide in the brain. Increasing evidence suggests that amyloid β peptide injures neurons both directly and indirectly by triggering neurotoxic innate immune responses. Myeloid differentiation factor 88 is the key signalling molecule downstream to most innate immune receptors crucial in inflammatory activation. For this reason, we investigated the effects of myeloid differentiation factor 88-deficient bone marrow cells on Alzheimer's disease-related symptoms and pathology by establishing bone marrow chimeric amyloid β peptide precursor transgenic mice, in which bone marrow cells differentiate into microglia and are recruited to amyloid β peptide deposits. We observed that myeloid differentiation factor 88-deficient bone marrow reconstruction reduced both inflammatory activation and amyloid β peptide burden in the brain. In addition, synaptophysin, a marker of neuronal integrity, was preserved and the expression of neuronal plasticity-related genes, ARC and NMDA-R1, was increased. Thus, myeloid differentiation factor 88-deficient microglia significantly improved the cognitive function of amyloid β peptide precursor protein transgenic mice. Myeloid differentiation factor 88-deficiency enhanced amyloid β peptide phagocytosis by microglia/macrophages and blunted toxic inflammatory activation. Both the expression of amyloid β peptide precursor protein and amyloid β peptide degrading enzymes and also the efflux of amyloid β peptide from brain parenchyma were unaffected by myeloid differentiation factor 88-deficient microglia. By contrast, the activity of β-secretase was increased. β-Secretase is expressed primarily in neurons, with relatively little expression in astrocytes and microglia. Therefore, microglial replenishment with myeloid differentiation factor 88-deficient bone marrow cells might improve cognitive functions in Alzheimer's disease mouse models by enhancing amyloid β peptide phagocytosis and reducing inflammatory activation. These results could offer a new therapeutic option that might delay the progression of Alzheimer's disease.
• 5.33

  Impact points

  Expression of ALS-linked SOD1 mutant increases the neurotoxic potential of microglia via TLR2.

  Yang Liu, Wenlin Hao, Alik Dawson, Shirong Liu, Klaus Fassbender

  The Journal of biological chemistry. 01/2009;

  Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, in which activated microglia overexpressing ALS-linked SOD1 mutants (mSOD1) are known to contribute to neuronal death. However, it is unclear how mSOD1 expression affects micoglial activation and subsequently damage neurons. ... [more] Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, in which activated microglia overexpressing ALS-linked SOD1 mutants (mSOD1) are known to contribute to neuronal death. However, it is unclear how mSOD1 expression affects micoglial activation and subsequently damage neurons. In this study, we created mSOD1-overexpressing BV-2 microglial cell lines. Following TLR2, but not TLR4 stimulation, we observed that overexpression of human SOD1 G93A, L8Q or G10V mutant, as compared to the wild-type SOD1 or a mock control, significantly enhanced microglial secretion of a neurotoxic cytokine, tumor necrosis factor-alpha (TNF-a), which was dependent on the NADPH-oxidase-mediated increased generation of reactive oxygen species (ROS). In further experiments, we demonstrated that mSOD1 expression regulated TNF-a secretion at a post-transcriptional level and involved ROS-sensitive TNF-a converting enzymes, e.g. ADAM10 and 17, which shed TNF-a from its membrane-anchored precursor. Together with a recent report that the function of SOD1, as a self-regulating redox sensor in NADPH oxidase-dependent ROS production, is lost due to its genetic mutations, we conclude that mSOD1 expression in ALS facilitates microglial neurotoxic inflammatory responses via TLR2, which is mediated by an uncontrolled ROS generation. The link, between mSOD1, innate immunity and NADPH oxidase, offers new opportunities in ALS therapies.
• 2.77

  Impact points

  Rwdd1, a thymus aging related molecule, is a new member of the intrinsically unstructured protein family.

  Ning Kang, Dai Chen, Li Wang, Lian Duan, Shirong Liu, Long Tang, Qingfeng Liu, Lianxian Cui, Wei He

  Cellular & molecular immunology. 11/2008; 5(5):333-9.

  We had previously identified a novel protein termed Rwdd1 whose expression in thymus is decreased in aged or oxidatively stressed mice. In the present study, we found that Rwdd1 expressed in both prokaryotic and eukaryotic cells showed a slower migration rate on SDS-PAGE gel. In addition, Rwdd1 was ... [more] We had previously identified a novel protein termed Rwdd1 whose expression in thymus is decreased in aged or oxidatively stressed mice. In the present study, we found that Rwdd1 expressed in both prokaryotic and eukaryotic cells showed a slower migration rate on SDS-PAGE gel. In addition, Rwdd1 was more sensitive to proteinase proteolysis. Furthermore, being a highly acidic protein which contains an RWD domain, Rwdd1 shared a high level of sequence similarity with Gir2, a member of the intrinsically unstructured protein (IUP). These findings suggest that Rwdd1 is a novel member of the IUP family.
• 2.77

  Impact points

  Identification and characterization of a novel thymus aging related protein rwdd1.

  Ning Kang, Lian Duan, Long Tang, Shi Rong Liu, Chun Man Li, Yong Hai Li, Qing-Feng Liu, Yu Hu, Lian Xian Cui, Wei He

  Cellular & molecular immunology. 09/2008; 5(4):279-85.

  By using DDRT-PCR and EST segment ligation, a novel mouse thymus involution related gene Rwdd1 was identified. The reading frame encoded a protein of 243 amino acid residues which contained an RWD domain at the N terminus. Rwdd1 expression in thymus was decreased in aged and oxidatively stressed mic... [more] By using DDRT-PCR and EST segment ligation, a novel mouse thymus involution related gene Rwdd1 was identified. The reading frame encoded a protein of 243 amino acid residues which contained an RWD domain at the N terminus. Rwdd1 expression in thymus was decreased in aged and oxidatively stressed mice. It was found to be expressed extensively in thymocytes and thymic epithelial cells. The expression level of Rwdd1 could affect the transactivation activity of androgen receptor (AR) in transiently transfected thymic epithelial cells. However, no direct interaction could be detected by fluorescence resonance energy transfer (FRET) analysis. In conclusion, Rwdd1 is a thymus involution related protein that may indirectly affect AR signaling pathway.