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Journal Article•DOI•

The Inflammasome Sensor, NLRP3, Regulates CNS Inflammation and Demyelination via Caspase-1 and Interleukin-18

Sushmita Jha1, Siddharth Y. Srivastava1, Willie June Brickey, Heather A. Iocca1, Arrel D. Toews, James P. Morrison2, Vivian S. Chen1, Vivian S. Chen3, Denis Gris1, Glenn K. Matsushima, Jenny P.-Y. Ting •
University of North Carolina at Chapel Hill1, Charles River Laboratories2, North Carolina State University3
24 Nov 2010-The Journal of Neuroscience (Society for Neuroscience)-Vol. 30, Iss: 47, pp 15811-15820
TL;DR: It is suggested that NLRP3 plays an important role in a model of multiple sclerosis by exacerbating CNS inflammation, and this is partly mediated by caspase-1 and IL-18.
Abstract: Inflammation is increasingly recognized as an important contributor to a host of CNS disorders; however, its regulation in the brain is not well delineated. Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 (NLRP3) is a key component of the inflammasome complex, which also includes ASC (apoptotic speck-containing protein with a card) and procaspase-1. Inflammasome formation can be triggered by membrane P2X(7)R engagement leading to cleavage-induced maturation of caspase-1 and interleukin-1β (IL-1β)/IL-18. This work shows that expression of the Nlrp3 gene was increased >100-fold in a cuprizone-induced demyelination and neuroinflammation model. Mice lacking the Nlrp3 gene (Nlrp3(-/-)) exhibited delayed neuroinflammation, demyelination, and oligodendrocyte loss in this model. These mice also showed reduced demyelination in the experimental autoimmune encephalomyelitis model of neuroinflammation. This outcome is also observed for casp1(-/-) and IL-18(-/-) mice, whereas IL-1β(-/-) mice were indistinguishable from wild-type controls, indicating that Nlrp3-mediated function is through caspase-1 and IL-18. Additional analyses revealed that, unlike the IL-1β(-/-) mice, which have been previously shown to show delayed remyelination, Nlrp3(-/-) mice did not exhibit delayed remyelination. Interestingly, IL-18(-/-) mice showed enhanced remyelination, thus providing a possible compensatory mechanism for the lack of a remyelination defect in Nlrp3(-/-) mice. These results suggest that NLRP3 plays an important role in a model of multiple sclerosis by exacerbating CNS inflammation, and this is partly mediated by caspase-1 and IL-18. Additionally, the therapeutic inhibition of IL-18 might decrease demyelination but enhance remyelination, which has broad implications for demyelinating diseases.
Citations
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Journal Article•DOI•
Activation and regulation of the inflammasomes

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Eicke Latz, T. Sam Xiao1, Andrea Stutz2•
National Institutes of Health1, University of Bonn2
01 Jun 2013-Nature Reviews Immunology
TL;DR: The complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response are discussed, and the similarities to another molecular signalling platform — the apoptosome — that monitors cellular health are highlighted.
Abstract: Inflammasomes are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. In this Review, we discuss the complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response, and we highlight the similarities to another molecular signalling platform - the apoptosome - that monitors cellular health. Extracellular regulatory mechanisms are discussed, as well as the intracellular control of inflammasome assembly, for example, via ion fluxes, free radicals and autophagy.

2,361 citations

Journal Article•DOI•
Inflammasomes: mechanism of action, role in disease, and therapeutics

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Haitao Guo1, Justin B. Callaway1, Jenny P.-Y. Ting1•
University of North Carolina at Chapel Hill1
01 Jul 2015-Nature Medicine
TL;DR: Increasing evidence in mouse models strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases.
Abstract: The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins. They have been implicated in a host of inflammatory disorders. Recent developments have greatly enhanced our understanding of the molecular mechanisms by which different inflammasomes are activated. Additionally, increasing evidence in mouse models, supported by human data, strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases. Finally, recent developments pointing toward promising therapeutics that target inflammasome activity in inflammatory diseases have been reported. This review will focus on these three areas of inflammasome research.

2,291 citations

Journal Article•DOI•
NLRP3 inflammasome and its inhibitors: a review.

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Bo-Zong Shao1, Zhe-Qi Xu1, Bin-Ze Han1, Ding-Feng Su1, Chong Liu1 •
Second Military Medical University1
05 Nov 2015-Frontiers in Pharmacology
TL;DR: The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP2 inflammaome inhibitors.
Abstract: Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3”. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome (CAPS), as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors.

561 citations

Cites background from "The Inflammasome Sensor, NLRP3, Reg..."

  • ...…and others has demonstrated that NLRP3 inflammasome activation contributes to progression of multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in animal models (Ming et al., 2002; Jha et al., 2010; Lalor et al., 2011; Inoue et al., 2012a,b; Shao et al., 2014)....

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  • ...Severity of multiple sclerosis in patients correlates closely with levels of IL-1β, IL-18, and caspase-1 (Ming et al., 2002; Jha et al., 2010; Lalor et al., 2011); the serum levels of both ILs and of active caspase-1 (p20) are elevated in mice with EAE (Inoue et al., 2012a,b)....

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Journal Article•DOI•
Inflammasomes in the CNS

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John G. Walsh1, Daniel A. Muruve2, Christopher Power1•
University of Alberta1, University of Calgary2
01 Feb 2014-Nature Reviews Neuroscience
TL;DR: The current understanding of the functions of different inflammasomes in the CNS and their roles in neurological diseases is reviewed.
Abstract: Since their discovery in 2002, inflammasomes have been shown to be crucial mediators of caspase 1 activation, interleukin-1β and interleukin-18 release, and pyroptotic cell death. This Review describes our current understanding of the functions of different inflammasomes in the CNS and their roles in neurological diseases. Microglia and macrophages in the CNS contain multimolecular complexes termed inflammasomes. Inflammasomes function as intracellular sensors for infectious agents as well as for host-derived danger signals that are associated with neurological diseases, including meningitis, stroke and Alzheimer's disease. Assembly of an inflammasome activates caspase 1 and, subsequently, the proteolysis and release of the cytokines interleukin-1β and interleukin-18, as well as pyroptotic cell death. Since the discovery of inflammasomes in 2002, there has been burgeoning recognition of their complexities and functions. Here, we review the current understanding of the functions of different inflammasomes in the CNS and their roles in neurological diseases.

509 citations

Journal Article•DOI•
The adverse effects of air pollution on the nervous system.

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Sermin Genc1, Zeynep Zadeoglulari, Stefan H. Fuss, Kursad Genc•
Dokuz Eylül University1
19 Feb 2012-Journal of Toxicology
TL;DR: Emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology.
Abstract: Exposure to ambient air pollution is a serious and common public health concern associated with growing morbidity and mortality worldwide. In the last decades, the adverse effects of air pollution on the pulmonary and cardiovascular systems have been well established in a series of major epidemiological and observational studies. In the recent past, air pollution has also been associated with diseases of the central nervous system (CNS), including stroke, Alzheimer's disease, Parkinson's disease, and neurodevelopmental disorders. It has been demonstrated that various components of air pollution, such as nanosized particles, can easily translocate to the CNS where they can activate innate immune responses. Furthermore, systemic inflammation arising from the pulmonary or cardiovascular system can affect CNS health. Despite intense studies on the health effects of ambient air pollution, the underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology. A better understanding of the mediators and mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system and mental health.

489 citations

Cites background from "The Inflammasome Sensor, NLRP3, Reg..."

  • ...The NLRP3 inflammasome also plays an important role in an experimental model of MS, which is mediated by caspase-1 and IL-18 [184]....

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  • ...The inflammasome orchestrates the activation of caspase precursors, which in turn, cleave the precursor forms of the cytokines as IL-1β, IL-18 and interleukin-33 (IL-33), which triggers an inflammatory response, or the release of toxins from glial and endothelial cells [179]....

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  • ...The NLRP3 inflammasome also plays an important role in an experimental model of MS, which is mediated by caspase-1 and IL-18 [184]....

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  • ...Abbreviations Aβ: Amyloid-beta AD: Alzheimer’s disease ARE: Antioxidant response element ApoE: Apolipoprotein E ASC: Apoptosis-associated speck-like protein containing a CARD BAEPs: Brainstem auditory evoked potentials BBB: Blood-brain barrier CB: Carbon black CNS: Central nervous system CAPs: Concentrated ambient air particles COX-2: Cyclooxygenase-2 DEPs: Diesel exhaust particles EEG: Electroencephalography ER: Endoplasmic reticulum ENPs: Engineered nanoparticles GFAP: Enhanced glial fibrillary acidic protein GSH: Glutathione GSTP1: Glutathione-S-transferase gene GSTM1: Glutathione S-transferase Mu 1 HDAC1: Histone deacetylase 1 iNOS: Inducible nitric oxide synthase IL-6: Interleukin-6 IL-1β: Interleukin-1beta IL-18: Interleukin 18 ICAM: Intercellular adhesion molecule LTA: Lipoteichoic acid MMP: Matrix metalloproteinases MCAO: Middle cerebral artery occlusion mtDNA: Mitochondrial DNA MAP: Mitogen-activated protein MAPK: Mitogen-activated protein kinaseMS: Multiple sclerosis LPS: Lipopolysaccharide NQO1: NAD(P)H dehydrogenase quinone 1 NMs: Nanomaterials NP: Nano-sized particulate NAC: N-acetylcysteine NFTs: Neurofibrillary tangles NO: Nitric oxide NFκB: Nuclear factor kappa B Nrf2: Nuclear factor (erythroid-derived 2)-like 2 NLRP3: Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 NTS: Nucleus tractus solitarius PRRs: Pattern Recognition Receptors PD: Parkinson’s disease PM: Particulate matter PAHs: Polycyclic aromatic hydrocarbons RNS: Reactive nitrogen species ROS: Reactive oxygen species ROFA: Residual oil fly ash WHO: World Health Organization TLR4: Toll-like receptor 4 TNFα: Tumor necrosis factor alpha UFPs: Ultrafine UPR: Unfolded protein response VEGF: Vascular endothelial growth factor VCAM: Vascular cell adhesion molecule VLM: Ventrolateral medulla....

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  • ...The inflammasome promotes the maturation of inflammatory cytokines such as IL-1β and interleukin 18 (IL-18)....

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References
More filters
Journal Article•DOI•
Gout-associated uric acid crystals activate the NALP3 inflammasome

[...]

Fabio Martinon1, Virginie Pétrilli1, Annick Mayor1, Aubry Tardivel1, Jürg Tschopp1 •
University of Lausanne1
09 Mar 2006-Nature
TL;DR: It is shown that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18 in mice deficient in the IL-1β receptor.
Abstract: Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

4,504 citations

"The Inflammasome Sensor, NLRP3, Reg..." refers background in this paper

  • ...…much interest as sensors of PAMPs (pathogen-associated molecular patterns) as well as DAMPs (damage-associated molecular patterns); however, their roles in CNS inflammatory disorders have not been extensively studied (Mariathasan et al., 2006; Martinon et al., 2006; Willingham et al., 2007)....

    [...]

  • ...…bacterial RNA and toxins (Kanneganti et al., 2006a,b), viruses (Allen et al., 2009; Thomas et al., 2009), ATP (Mariathasan et al., 2006), uric acid (Martinon et al., 2006), hyaluronan (Yamasaki et al., 2009), amyloid- (Halle et al., 2008), asbestos, silica (Dostert et al., 2008; Hornung et al.,…...

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Journal Article•DOI•
Microglia: active sensor and versatile effector cells in the normal and pathologic brain

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Uwe-Karsten Hanisch1, Helmut Kettenmann2•
University of Göttingen1, Max Delbrück Center for Molecular Medicine2
01 Nov 2007-Nature Neuroscience
TL;DR: This review focuses on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.
Abstract: Microglial cells constitute the resident macrophage population of the CNS. Recent in vivo studies have shown that microglia carry out active tissue scanning, which challenges the traditional notion of 'resting' microglia in the normal brain. Transformation of microglia to reactive states in response to pathology has been known for decades as microglial activation, but seems to be more diverse and dynamic than ever anticipated—in both transcriptional and nontranscriptional features and functional consequences. This may help to explain why engagement of microglia can be either neuroprotective or neurotoxic, resulting in containment or aggravation of disease progression. Moreover, little is known about the heterogeneity of microglial responses in different pathologic contexts that results from regional adaptations or from the progression of a disease. In this review, we focus on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.

3,238 citations

"The Inflammasome Sensor, NLRP3, Reg..." refers background in this paper

  • ...Activated microglia can phagocytose cellular debris, present antigens to T-cells, and release cytokines and chemokines (Hanisch and Kettenmann, 2007; Napoli and Neumann, 2009)....

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  • ...Microglia are resident immune cells of the CNS (Hanisch and Kettenmann, 2007)....

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Journal Article•DOI•
Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.

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Claudia F. Lucchinetti1, Wolfgang Brück2, Joseph E. Parisi1, Bernd W. Scheithauer1, Moses Rodriguez1, Hans Lassmann3 •
Mayo Clinic1, University of Göttingen2, University of Vienna3
01 Jun 2000-Annals of Neurology
TL;DR: At a given time point of the disease, the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient, suggesting that MS may be a disease with heterogeneous pathogenetic mechanisms.
Abstract: Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell‐mediated or T-cell plus antibody‐mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease—as reflected in autopsy cases—the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease.

3,162 citations

"The Inflammasome Sensor, NLRP3, Reg..." refers background in this paper

  • ...…advantages: (1) it exhibits type III and IV MS neuropathology characterized by microglial infiltration and astrogliosis without T-cell infiltrates (Lucchinetti et al., 2000; Liu et al., 2010), (2) it is easily induced by administering cuprizone through the chow, (3) the disease course follows a…...

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  • ...This model has several advantages: (1) it exhibits type III and IV MS neuropathology characterized by microglial infiltration and astrogliosis without T-cell infiltrates (Lucchinetti et al., 2000; Liu et al., 2010), (2) it is easily induced by administering cuprizone through the chow, (3) the disease course follows a predictable time course and pathology, and (4) remyelination can be initiated by withdrawing the cuprizone (Matsushima and Morell, 2001)....

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Journal Article•DOI•
Cryopyrin activates the inflammasome in response to toxins and ATP

[...]

Sanjeev Mariathasan1, David S. Weiss2, Kim Newton, Jacqueline McBride1, Karen O'Rourke, Meron Roose-Girma, Wyne P. Lee1, Yvette Weinrauch3, Denise M. Monack2, Vishva M. Dixit •
Genentech1, Stanford University2, New York University3
09 Mar 2006-Nature
TL;DR: It is shown that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels.
Abstract: A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

2,789 citations

"The Inflammasome Sensor, NLRP3, Reg..." refers background in this paper

  • ...NLRP3 forms an inflammasome in response to bacterial RNA and toxins (Kanneganti et al., 2006a,b), viruses (Allen et al., 2009; Thomas et al., 2009), ATP (Mariathasan et al., 2006), uric acid (Martinon et al., 2006), hyaluronan (Yamasaki et al., 2009), amyloid- (Halle et al., 2008), asbestos, silica (Dostert et al., 2008; Hornung et al., 2008), and alum (Hornung et al., 2008; Li et al., 2008)....

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  • ...(damage-associated molecular patterns); however, their roles in CNS inflammatory disorders have not been extensively studied (Mariathasan et al., 2006; Martinon et al., 2006; Willingham et al., 2007)....

    [...]

  • ...A lack of a difference in TNF- is typical of NLRP3deficient mice (Mariathasan et al., 2006; Sutterwala et al., 2006a)....

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  • ...…forms an inflammasome in response to bacterial RNA and toxins (Kanneganti et al., 2006a,b), viruses (Allen et al., 2009; Thomas et al., 2009), ATP (Mariathasan et al., 2006), uric acid (Martinon et al., 2006), hyaluronan (Yamasaki et al., 2009), amyloid- (Halle et al., 2008), asbestos, silica…...

    [...]

  • ...…much interest as sensors of PAMPs (pathogen-associated molecular patterns) as well as DAMPs (damage-associated molecular patterns); however, their roles in CNS inflammatory disorders have not been extensively studied (Mariathasan et al., 2006; Martinon et al., 2006; Willingham et al., 2007)....

    [...]

Journal Article•DOI•
Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization

[...]

Veit Hornung1, Franz Bauernfeind2, Annett Halle1, Eivind O. Samstad3, Eivind O. Samstad1, Hajime Kono1, Kenneth L. Rock1, Katherine A. Fitzgerald1, Eicke Latz3, Eicke Latz1 •
University of Massachusetts Medical School1, Ludwig Maximilian University of Munich2, Norwegian University of Science and Technology3
11 Jul 2008-Nature Immunology
TL;DR: It is demonstrated that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3, which senses lysosomal damage as an endogenous 'danger' signal.
Abstract: Inhalation of silica crystals causes inflammation in the alveolar space. Prolonged exposure to silica can lead to the development of silicosis, an irreversible, fibrotic pulmonary disease. The mechanisms by which silica and other crystals activate immune cells are not well understood. Here we demonstrate that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3. NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. 'Sterile' lysosomal damage (without crystals) also induced NALP3 activation, and inhibition of either phagosomal acidification or cathepsin B activity impaired NALP3 activation. Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal.

2,625 citations

"The Inflammasome Sensor, NLRP3, Reg..." refers background in this paper

  • ...The Inflammasome Sensor, NLRP3, Regulates CNS...

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  • ...…viruses (Allen et al., 2009; Thomas et al., 2009), ATP (Mariathasan et al., 2006), uric acid (Martinon et al., 2006), hyaluronan (Yamasaki et al., 2009), amyloid- (Halle et al., 2008), asbestos, silica (Dostert et al., 2008; Hornung et al., 2008), and alum (Hornung et al., 2008; Li et al., 2008)....

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