Eicke Latz

Publications (81)951.28 Total impact

• Source

  Available from: Jörg Günter Grossmann

  Dataset: 2009 JBC Myddosome suppl

  Precious G. Motshwene, Martin C. Moncrieffe, J. Günter Grossmann, Cheng Kao, Murali Ayaluru, Alan M. Sandercock, Carol V. Robinson, Eicke Latz, Nicholas J. Gay
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  Available from: Eva Bartok

  Article: iGLuc: a luciferase-based inflammasome and protease activity reporter.

  Eva Bartok, Franz Bauernfeind, Maria G Khaminets, Christopher Jakobs, Brian Monks, Katherine A Fitzgerald, Eicke Latz, Veit Hornung
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  ABSTRACT: Measurement of protease activity in living cells or organisms remains a challenging task. We here present a transgene-encoded biosensor that reports the proteolytic activity of caspase-1 in the course of inflammasome activation and that of other proteases in a highly sensitive and specific manner. This protease reporter is based on the biological activity of a pro-interleukin (IL)-1β-Gaussia luciferase (iGLuc) fusion construct, in which pro-IL-1β-dependent formation of protein aggregates renders GLuc enzyme inactive. Cleavage leads to monomerization of this biosensor protein, resulting in a strong gain in luciferase activity. Exchange of the canonical caspase-1 cleavage site in this reporter construct allows the generation of protease biosensors with additional specificities. The high sensitivity, signal-to-background ratio and specificity of the iGLuc system renders it a useful tool to study proteolytic events in mouse and human cells at high throughput and to monitor protease activity in mice in vivo.
  Nature Methods 01/2013; · 19.28 Impact Factor
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  Available from: Kazuhiro Aoki

  Dataset: Asagiri.SOM

  Masataka Asagiri, Toshitake Hirai, Toshihiro Kunigami, Shunya Kamano, Hans-Jürgen Gober, Kazuo Okamoto, Keizo Nishikawa, Eicke Latz, Douglas T Golenbock, Kazuhiro Aoki, Keiichi Ohya, Yuuki Imai, Yasuyuki Morishita, Kohei Miyazono, Shigeaki Kato, Paul Saftig, Hiroshi Takayanagi
• Article: Noncanonical Autophagy Is Required for Type I Interferon Secretion in Response to DNA-Immune Complexes.

  Jill Henault, Jennifer Martinez, Jeffrey M Riggs, Jane Tian, Payal Mehta, Lorraine Clarke, Miwa Sasai, Eicke Latz, Melanie M Brinkmann, Akiko Iwasaki, Anthony J Coyle, Roland Kolbeck, Douglas R Green, Miguel A Sanjuan
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  ABSTRACT: Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment.
  Immunity 12/2012; · 21.64 Impact Factor
• Article: Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1β and IL-18 Maturation via Caspase-8 in an RIP3-Independent Manner.

  Lukas Bossaller, Ping-I Chiang, Christian Schmidt-Lauber, Sandhya Ganesan, William J Kaiser, Vijay A K Rathinam, Edward S Mocarski, Deepa Subramanian, Douglas R Green, Neal Silverman, Katherine A Fitzgerald, Ann Marshak-Rothstein, Eicke Latz
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  ABSTRACT: Fas, a TNF family receptor, is activated by the membrane protein Fas ligand expressed on various immune cells. Fas signaling triggers apoptosis and induces inflammatory cytokine production. Among the Fas-induced cytokines, the IL-1β family cytokines require proteolysis to gain biological activity. Inflammasomes, which respond to pathogens and danger signals, cleave IL-1β cytokines via caspase-1. However, the mechanisms by which Fas regulates IL-1β activation remain unresolved. In this article, we demonstrate that macrophages exposed to TLR ligands upregulate Fas, which renders them responsive to receptor engagement by Fas ligand. Fas signaling activates caspase-8 in macrophages and dendritic cells, leading to the maturation of IL-1β and IL-18 independently of inflammasomes or RIP3. Hence, Fas controls a novel noncanonical IL-1β activation pathway in myeloid cells, which could play an essential role in inflammatory processes, tumor surveillance, and control of infectious diseases.
  The Journal of Immunology 11/2012; · 5.79 Impact Factor
• Article: Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor.

  Tengchuan Jin, Andrew Perry, Jiansheng Jiang, Patrick Smith, James A Curry, Leonie Unterholzner, Zhaozhao Jiang, Gabor Horvath, Vijay A Rathinam, Ricky W Johnstone, Veit Hornung, Eicke Latz, Andrew G Bowie, Katherine A Fitzgerald, T Sam Xiao
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  ABSTRACT: Recognition of DNA by the innate immune system is central to antiviral and antibacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence-specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
  Immunity 04/2012; 36(4):561-71. · 21.64 Impact Factor
• Article: Direct measurement of the interaction force between immunostimulatory CpG-DNA and TLR9 fusion protein.

  Dionne C G Klein, Kirsti Marie Øvrebø, Eicke Latz, Terje Espevik, Bjørn T Stokke
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  ABSTRACT: The specific interaction between human Toll-like receptor 9 (TLR9)-ectodomain (ECD)-fusion protein and immunostimulatory CpG-DNA was measured using force spectroscopy. Flexible tethers were used between receptors and surface as well as between DNA and atomic force microscope tip to make efficient recognition studies possible. The molecular recognition forces detected are in the range of 50 to 150 ± 20 pN at the used force-loading rates, and the molecular interaction probability was much reduced when the receptors were blocked with free CpG-DNA. A linear increase of the unbinding force with the logarithm of the loading rate was found over the range 0.1 to 30 nN/s. This indicates a single potential barrier characterizing the energy landscape and no intermediate state for the unbinding pathway of CpG-DNA from the TLR9-ECD. Two important kinetic parameters for CpG-DNA interaction with TLR9-ECD were determined from the force-loading rate dependency: an off-rate of k(off) = 0.14 ± 0.10 s(-1) and a binding interaction length of x(β) = 0.30 ± 0.03 nm, which are consistent with literature values. Various models for the molecular interaction of this innate immune receptor binding to CpG-DNA are discussed.
  Journal of Molecular Recognition 02/2012; 25(2):74-81. · 3.31 Impact Factor
• Article: Intracellular sensing of microbes and danger signals by the inflammasomes.

  Gabor L Horvath, Jacob E Schrum, Christine M De Nardo, Eicke Latz
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  ABSTRACT: The cells of the innate immune system mobilize a coordinated immune response towards invading microbes and after disturbances in tissue homeostasis. These immune responses typically lead to infection control and tissue repair. Exaggerated or uncontrolled immune responses, however, can also induce acute of chronic inflammatory pathologies that are characteristic for many common diseases such as sepsis, arthritis, atherosclerosis, or Alzheimer's disease. In recent years, the concerted efforts of many scientists have uncovered numerous mechanisms by which immune cells detect foreign or changed self-substances that appear in infections or during tissue damage. These substances stimulate signaling receptors, which leads to cellular activation and the induction of effector mechanisms. Here, we review the role of inflammasomes, a family of signaling molecules that form multi-molecular signaling platforms and activate inflammatory caspases and interleukin-1β cytokines.
  Immunological Reviews 09/2011; 243(1):119-35. · 11.15 Impact Factor
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  Available from: Eva Bartok

  Article: Critical role of nucleotide-binding oligomerization domain-like receptor 3 in vascular repair.

  Sebastian Schlaweck, Sebastian Zimmer, Rafael Struck, Eva Bartok, Nikos Werner, Franz Bauernfeind, Eicke Latz, Georg Nickenig, Veit Hornung, Alexander Ghanem
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  ABSTRACT: Vascular remodeling characterized by hyperproliferative neointima formation is an unfavorable repair process that is triggered by vascular damage. This process is characterized by an increased local inflammatory and proliferative response that critically involves the pro-inflammatory cytokine interleukin-1β (IL-1β). IL-1β is expressed and cytosolically retained as a procytokine that requires additional processing prior to exerting its pro-inflammatory function. Maturation and release of pro IL-1β is governed by a cytosolic protein scaffold that is known as the inflammasome. Here we show that NLRP3 (NOD-like receptor family, pryin domain containing 3), an important activating component of the inflammasome, is involved in neointima formation after vascular injury. NLRP3 deficiency itself does not affect the functional cardiovascular phenotype and does not alter peripheral differential blood counts. However, neointima development following wire injury of the carotid artery was significantly decreased in NLRP3-deficient mice as compared to wild-type controls. In all, NLRP3 plays a non-redundant role in vascular damage mediated neointima formation. Our data establish NLRP3 as a key player in the response to vascular damage, which could open new avenues to therapeutic intervention.
  Biochemical and Biophysical Research Communications 08/2011; 411(3):627-31. · 2.48 Impact Factor
• Article: NLRP3 inflammasomes link inflammation and metabolic disease.

  Dominic De Nardo, Eicke Latz
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  ABSTRACT: A strong link between inflammation and metabolism is becoming increasingly evident. A number of recent landmark studies have implicated the activation of the NLRP3 inflammasome, an interleukin-1β family cytokine-activating protein complex, in a variety of metabolic diseases including obesity, atherosclerosis and type 2 diabetes. Here, we review these new developments and discuss their implications for a better understanding of inflammation in metabolic disease, and the prospects of targeting the NLRP3 inflammasome for therapeutic intervention.
  Trends in Immunology 08/2011; 32(8):373-9. · 10.40 Impact Factor
• Article: Getting closer to the dirty little secret.

  Karin Pelka, Eicke Latz
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  ABSTRACT: The molecular mechanism behind alum adjuvanticity is probably the oldest secret of immunology. In this issue of Immunity, Kuroda et al. (2011) and Kool et al. (2011) identify NLRP3 inflammasome-independent signaling to be crucial for the Th2 cell response induced by aluminum salts.
  Immunity 04/2011; 34(4):455-8. · 21.64 Impact Factor
• Article: Natural loss-of-function mutation of myeloid differentiation protein 88 disrupts its ability to form Myddosomes.

  Kamalpreet Nagpal, Theo S Plantinga, Cherilyn M Sirois, Brian G Monks, Eicke Latz, Mihai G Netea, Douglas T Golenbock
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  ABSTRACT: Myeloid differentiation protein 88 (MyD88) is a key signaling adapter in Toll-like receptor (TLR) signaling. MyD88 is also one of the most polymorphic adapter proteins. We screened the reported nonsynonymous coding mutations in MyD88 to identify variants with altered function. In reporter assays, a death domain variant, S34Y, was found to be inactive. Importantly, in reconstituted macrophage-like cell lines derived from knock-out mice, MyD88 S34Y was severely compromised in its ability to respond to all MyD88-dependent TLR ligands. Unlike wild-type MyD88, S34Y is unable to form distinct foci in the cells but is present diffused in the cytoplasm. We observed that IRAK4 co-localizes with MyD88 in these aggregates, and thus these foci appear to be "Myddosomes." The MyD88 S34Y loss-of-function mutant demonstrates how proper cellular localization of MyD88 to the Myddosome is a feature required for MyD88 function.
  Journal of Biological Chemistry 02/2011; 286(13):11875-82. · 4.77 Impact Factor
• Article: Innate immune receptors for nucleic acids.

  Andrea Stutz, Damien Bertheloot, Eicke Latz
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  ABSTRACT: The innate immune system has evolved to detect microbes and sterile tissue damage with the help of a series of signaling receptors. One key strategy is to detect infectious microbes or host cell damage by recognizing nucleic acids that are modified or appear in compartment normally devoid of nucleic acids. Here, we describe two methods that allow studying the molecular interaction between various nucleic acid recognizing signaling receptors with their ligands. A ligand pull-down assay can be used to show a known interaction between a ligand and its receptor or the method can be utilized as a discovery approach to identify an unknown receptor to a given ligand. An AlphaScreen experiment can be set up to assess the ligand binding affinity to a given receptor.
  Methods in molecular biology (Clifton, N.J.) 01/2011; 748:69-82.
• Source

  Available from: Tsan Xiao

  Article: IFI16 is an innate immune sensor for intracellular DNA.

  Leonie Unterholzner, Sinead E Keating, Marcin Baran, Kristy A Horan, Søren B Jensen, Shruti Sharma, Cherilyn M Sirois, Tengchuan Jin, Eicke Latz, T Sam Xiao, Katherine A Fitzgerald, Søren R Paludan, Andrew G Bowie
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  ABSTRACT: The detection of intracellular microbial DNA is critical to appropriate innate immune responses; however, knowledge of how such DNA is sensed is limited. Here we identify IFI16, a PYHIN protein, as an intracellular DNA sensor that mediates the induction of interferon-β (IFN-β). IFI16 directly associated with IFN-β-inducing viral DNA motifs. STING, a critical mediator of IFN-β responses to DNA, was recruited to IFI16 after DNA stimulation. Lowering the expression of IFI16 or its mouse ortholog p204 by RNA-mediated interference inhibited gene induction and activation of the transcription factors IRF3 and NF-κB induced by DNA and herpes simplex virus type 1 (HSV-1). IFI16 (p204) is the first PYHIN protein to our knowledge shown to be involved in IFN-β induction. Thus, the PYHIN proteins IFI16 and AIM2 form a new family of innate DNA sensors we call 'AIM2-like receptors' (ALRs).
  Nature Immunology 10/2010; 11(11):997-1004. · 26.01 Impact Factor
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  Available from: Harald Husebye

  Article: The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes.

  Harald Husebye, Marie Hjelmseth Aune, Jørgen Stenvik, Eivind Samstad, Frode Skjeldal, Oyvind Halaas, Nadra J Nilsen, Harald Stenmark, Eicke Latz, Egil Lien, Tom Eirik Mollnes, Oddmund Bakke, Terje Espevik
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  ABSTRACT: Toll-like receptor 4 (TLR4) is indispensable for recognition of Gram-negative bacteria. We described a trafficking pathway for TLR4 from the endocytic recycling compartment (ERC) to E. coli phagosomes. We found a prominent colocalization between TLR4 and the small GTPase Rab11a in the ERC, and Rab11a was involved in the recruitment of TLR4 to phagosomes in a process requiring TLR4 signaling. Also, Toll-receptor-associated molecule (TRAM) and interferon regulatory factor-3 (IRF3) localized to E. coli phagosomes and internalization of E. coli was required for a robust interferon-β induction. Suppression of Rab11a reduced TLR4 in the ERC and on phagosomes leading to inhibition of the IRF3 signaling pathway induced by E. coli, whereas activation of the transcription factor NF-κB was unaffected. Moreover, Rab11a silencing reduced the amount of TRAM on phagosomes. Thus, Rab11a is an important regulator of TLR4 and TRAM transport to E. coli phagosomes thereby controlling IRF3 activation from this compartment.
  Immunity 10/2010; 33(4):583-96. · 21.64 Impact Factor
• Article: NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.

  Peter Duewell, Hajime Kono, Katey J Rayner, Cherilyn M Sirois, Gregory Vladimer, Franz G Bauernfeind, George S Abela, Luigi Franchi, Gabriel Nuñez, Max Schnurr, Terje Espevik, Egil Lien, Katherine A Fitzgerald, Kenneth L Rock, Kathryn J Moore, Samuel D Wright, Veit Hornung, Eicke Latz
  Nature 07/2010; 466(7306):652. · 36.28 Impact Factor
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  Available from: Emily Lowe

  Article: Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling.

  Pearl Gray, Kathrin S Michelsen, Cherilyn M Sirois, Emily Lowe, Kenichi Shimada, Timothy R Crother, Shuang Chen, Constantinos Brikos, Yonca Bulut, Eicke Latz, David Underhill, Moshe Arditi
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  ABSTRACT: Myeloid differentiation factor 2 (MD-2) is a secreted gp that assembles with TLR4 to form a functional signaling receptor for bacterial LPS. In this study, we have identified a novel alternatively spliced isoform of human MD-2, termed MD-2 short (MD-2s), which lacks the region encoded by exon 2 of the MD-2 gene. Similar to MD-2, MD-2s is glycosylated and secreted. MD-2s also interacted with LPS and TLR4, but failed to mediate LPS-induced NF-kappaB activation and IL-8 production. We show that MD-2s is upregulated upon IFN-gamma, IL-6, and TLR4 stimulation and negatively regulates LPS-mediated TLR4 signaling. Furthermore, MD-2s competitively inhibited binding of MD-2 to TLR4. Our study pinpoints a mechanism that may be used to regulate TLR4 activation at the onset of signaling and identifies MD-2s as a potential therapeutic candidate to treat human diseases characterized by an overly exuberant or chronic immune response to LPS.
  The Journal of Immunology 06/2010; 184(11):6359-66. · 5.79 Impact Factor
• Article: Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome.

  Christian Bauer, Peter Duewell, Christine Mayer, Hans Anton Lehr, Katherine A Fitzgerald, Marc Dauer, Jurg Tschopp, Stefan Endres, Eicke Latz, Max Schnurr
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  ABSTRACT: The proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined. IL-1beta production in response to DSS was studied in macrophages of wild-type, caspase-1(-/-), NLRP3(-/-), ASC(-/-), cathepsin B(-/-) or cathepsin L(-/-) mice. Colitis was induced in C57BL/6 and NLRP3(-/-) mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue. Macrophages incubated with DSS in vitro secreted high levels of IL-1beta in a caspase-1-dependent manner. IL-1beta secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1beta secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3(-/-) mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency. The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.
  Gut 05/2010; 59(9):1192-9. · 10.11 Impact Factor
• Article: The sterile inflammatory response.

  Kenneth L Rock, Eicke Latz, Fernando Ontiveros, Hajime Kono
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  ABSTRACT: The acute inflammatory response is a double-edged sword. On the one hand, it plays a key role in initial host defense, particularly against many infections. On the other hand, its aim is imprecise, and as a consequence, when it is drawn into battle, it can cause collateral damage in tissues. In situations where the inciting stimulus is sterile, the cost-benefit ratio may be high; because of this, sterile inflammation underlies the pathogenesis of a number of diseases. Although there have been major advances in our understanding of how microbes trigger inflammation, much less has been learned about this process in sterile situations. This review focuses on a subset of the many sterile stimuli that can induce inflammation-specifically dead cells and a variety of irritant particles, including crystals, minerals, and protein aggregates. Although this subset of stimuli is structurally very diverse and might appear to be unrelated, there is accumulating evidence that the innate immune system may recognize them in similar ways and stimulate the sterile inflammatory response via common pathways. Here we review established and emerging data about these responses.
  Annual Review of Immunology 04/2010; 28:321-42. · 52.76 Impact Factor
• Article: Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome.

  Christine Juliana, Teresa Fernandes-Alnemri, Jianghong Wu, Pinaki Datta, Leobaldo Solorzano, Je-Wook Yu, Rong Meng, Andrew A Quong, Eicke Latz, Charles P Scott, Emad S Alnemri
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  ABSTRACT: Activation of the inflammasome generates the pro-inflammatory cytokines interleukin-1 beta and -18, which are important mediators of inflammation. Abnormal activation of the inflammasome leads to many inflammatory diseases, including gout, silicosis, neurodegeneration, and genetically inherited periodic fever syndromes. Therefore, identification of small molecule inhibitors that target the inflammasome is an important step toward developing effective therapeutics for the treatment of inflammation. Here, we show that the herbal NF-kappaB inhibitory compound parthenolide inhibits the activity of multiple inflammasomes in macrophages by directly inhibiting the protease activity of caspase-1. Additional investigations of other NF-kappaB inhibitors revealed that the synthetic I kappaB kinase-beta inhibitor Bay 11-7082 and structurally related vinyl sulfone compounds selectively inhibit NLRP3 inflammasome activity in macrophages independent of their inhibitory effect on NF-kappaB activity. In vitro assays of the effect of parthenolide and Bay 11-7082 on the ATPase activity of NLRP3 demonstrated that both compounds inhibit the ATPase activity of NLRP3, suggesting that the inhibitory effect of these compounds on inflammasome activity could be mediated in part through their effect on the ATPase activity of NLRP3. Our results thus elucidate the molecular mechanism for the therapeutic anti-inflammatory activity of parthenolide and identify vinyl sulfones as a new class of potential therapeutics that target the NLRP3 inflammasome.
  Journal of Biological Chemistry 03/2010; 285(13):9792-802. · 4.77 Impact Factor