Abstract
As explained in Chap. 2, mechanistic causal models of how effects propagate through a system typically require more detailed information to build and validate than other forms of causal analysis, including predictive and attributive causal modeling. Substantial applied and computational mathematical research, modeling, and algorithm development is sometimes needed to describe with useful accuracy how a system evolves over time. On the other hand, mathematical analysis can also reveal robust qualitative properties of a system’s dynamic response to inputs. For example, many complex feedback control networks exhibit the qualitative property of bistability, in which a sufficiently long and intense stimulus or exogenous input causes the system to shift from its normal state to a new one with different properties that then becomes the new stable state of the system. Such stimulus-driven switches in behaviors occur frequently in biological regulatory networks and in other (e.g., socioeconomic) systems with positive feedback loops. This chapter considers the implications of recent advances in molecular biological understanding of the causal mechanisms of inflammation-mediated diseases for quantitative dose-response modeling. It focuses on the dynamic behavior of the NLRP3 (nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing) inflammasome, a signaling complex that is activated in response to sufficiently large exposures to potentially injurious agents including Staphylococcus aureus or Listeria monocytogenes bacteria, influenza and other viruses, radiation, asbestos fibers, and respirable crystalline silica (RCS) and that has been implicated in a host of inflammation-mediated diseases including asbestosis, fibrosis, mesothelioma, lung cancer, heart disease, gout, arthritis, and diabetes. Given this large and diverse array of agents and diseases for which NRLP3 provides a key to pathological responses, we will focus on how mineral particles and fibers such as asbestoscan activate the NRLP3 inflamasome and on the consequences for the shape of the dose-response relationship for inflammation-mediated responses to exposure.
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References
Andersen ME, Preston RJ, Maier A, Willis AM, Patterson J (2014) Dose-response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: results of a workshop. Crit Rev Toxicol 44(1):50–63. https://doi.org/10.3109/10408444.2013.835785
Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout GB, Bahar I (2006) Bistability in apoptosis: roles of bax, bcl-2, and mitochondrial permeability transition pores. Biophys J 90(5):1546–1559
Baroja-Mazo A, Martín-Sánchez F, Gomez AI, Martínez CM, Amores-Iniesta J, Compan V, Barberà-Cremades M, Yagüe J, Ruiz-Ortiz E, Antón J, Buján S, Couillin I, Brough D, Arostegui JI, Pelegrín P (2014) The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 15(8):738–748. https://doi.org/10.1038/ni.2919
Bednash JS, Mallampalli RK (2016) Regulation of inflammasomes by ubiquitination. Cell Mol Immunol 13(6):722–728. https://doi.org/10.1038/cmi.2016.15
Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27(50):6434–6451. https://doi.org/10.1038/onc.2008.310
Chakravarty S, Barik D (2017) Steady state statistical correlations predict bistability in reaction motifs. Mol Biosyst 13(4):775–784. https://doi.org/10.1039/c7mb00052a
Cox LA Jr (2006) Universality of J-shaped and U-shaped dose-response relations as emergent properties of stochastic transition systems. Dose Response 3(3):353–368. https://doi.org/10.2203/dose-response.0003.03.006
Cox LA Jr (2011) A causal model of chronic obstructive pulmonary disease (COPD) risk. Risk Analysis 31(1):38–62
Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A, Engels G, Brenker C, Nordhoff M, Mirandola SR, Al-Amoudi A, Mangan MS, Zimmer S, Monks BG, Fricke M, Schmidt RE, Espevik T, Jones B, Jarnicki AG, Hansbro PM, Busto P, Marshak-Rothstein A, Hornemann S, Aguzzi A, Kastenmüller W, Latz E (2014) The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat Immunol 15(8):727–737. https://doi.org/10.1038/ni.2913
Gottschalk RA, Martins AJ, Angermann BR, Dutta B, Ng CE, Uderhardt S, Tsang JS, Fraser ID, Meier-Schellersheim M, Germain RN (2016) Distinct NF-κB and MAPK activation thresholds uncouple steady-state microbe sensing from anti-pathogen inflammatory responses. Cell Syst 2(6):378–390. https://doi.org/10.1016/j.cels.2016.04.016
Guisoni N, Loscar ES, Albano EV (2011) Phase diagram and critical behavior of a forest-fire model in a gradient of immunity. Phys Rev E Stat Nonlin Soft Matter Phys. 83(1 Pt 1):011125
Guo H, Callaway JB, Ting JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21(7):677–687. https://doi.org/10.1038/nm.3893
Harijith A, Ebenezer DL, Natarajan V (2014) Reactive oxygen species at the crossroads of inflammasome and inflammation. Front Physiol 5:352. https://doi.org/10.3389/fphys.2014.003
Hillegass JM, Miller JM, MacPherson MB, Westbom CM, Sayan M, Thompson JK, Macura SL, Perkins TN, Beuschel SL, Alexeeva V, Pass HI, Steele C, Mossman BT, Shukla A (2013) Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells. Part Fibre Toxicol 10:39. https://doi.org/10.1186/1743-8977-10-39
Jin S, Li Y, Pan R, Zou X (2014) Characterizing and controlling the inflammatory network during influenza A virus infection. Sci Rep 4:3799. https://doi.org/10.1038/srep03799
Li X, Levine H (2017) Bistability of the cytokine-immune cell network in a cancer microenvironment. Converg Sci Phys Oncol 3(2):28. http://iopscience.iop.org/article/10.1088/2057-1739/aa6c07
Malka R, Shochat E, Rom-Kedar V (2010) Bistability and bacterial infections. PLoS One 5(5):e10010. https://doi.org/10.1371/journal.pone.0010010
Nakamura K, Kawakami T, Yamamoto N, Tomizawa M, Fujiwara T, Ishii T, Harigae H, Ogasawara K (2016) Activation of the NLRP3 inflammasome by cellular labile iron. Exp Hematol 44(2):116–124. https://doi.org/10.1016/j.exphem.2015.11.002
Okada M, Matsuzawa A, Yoshimura A, Ichijo H (2014) The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation. J Biol Chem 289(47):32926–32936. https://doi.org/10.1074/jbc.M114.579961
Pereira EJ, Smolko CM, Janes KA (2016) Computational models of reactive oxygen species as metabolic byproducts and signal-transduction modulators. Front Pharmacol 7:457
Py BF, Kim MS, Vakifahmetoglu-Norberg H, Yuan J (2013) Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell 49(2):331–338. https://doi.org/10.1016/j.molcel.2012.11.009
Qiao Q, Wu H (2015) Supramolecular organizing centers (SMOCs) as signaling machines in innate immune activation. Sci China Life Sci 58(11):1067–1072. https://doi.org/10.1007/s11427-015-4951-z
Repnik U, Hafner Česen M, Turk B (2014) Lysosomal membrane permeabilization in cell death: concepts and challenges. Mitochondrion 19 Pt A:49–57. https://doi.org/10.1016/j.mito.2014.06.006
Sayan M, Mossman BT (2016) The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases. Part Fibre Toxicol 13(1):51. https://doi.org/10.1186/s12989-016-0162-4
Schilling JD (2016) Dousing fire with gasoline: interplay between lysosome damage and the NLRP3 inflammasome. Focus on “NLRP3 inflammasome signaling is activated by low-level lysosome disruption but inhibited by extensive lysosome disruption: roles for K+ efflux and Ca2+ influx”. Am J Physiol Cell Physiol 311(1):C81–C82. https://doi.org/10.1152/ajpcell.00174.2016
Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C (2015) NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol 6:262. https://doi.org/10.3389/fphar.2015.00262
Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH (2012) Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13(3):255–263
Siegal-Gaskins D, Mejia-Guerra MK, Smith GD, Grotewold E (2011) Emergence of switch-like behavior in a large family of simple biochemical networks. PLoS Comput Biol 7(5):e1002039. https://doi.org/10.1371/journal.pcbi.1002039
Squires S, Sytwu K, Alcala D, Antonsen TM, Ott E, Girvan M (2013) Weakly explosive percolation in directed networks. Phys Rev E Stat Nonlin Soft Matter Phys 87(5):052127
Thompson JK, Westbom CM, MacPherson MB, Mossman BT, Heintz NH, Spiess P, Shukla A (2014) Asbestos modulates thioredoxin-thioredoxin interacting protein interaction to regulate inflammasome activation. Part Fibre Toxicol 11:24. https://doi.org/10.1186/1743-8977-11-24
Thompson JK, MacPherson MB, Beuschel SL, Shukla A (2017) Asbestos-induced mesothelial to fibroblastic transition is modulated by the inflammasome. Am J Pathol 187(3):665–678. https://doi.org/10.1016/j.ajpath.2016.11.008
Veltman D, Laeremans T, Passante E, Huber HJ (2017) Signal transduction analysis of the NLRP3-inflammasome pathway after cellular damage and its paracrine regulation. J Theor Biol 415:125–136. https://doi.org/10.1016/j.jtbi.2016.12.016
Wu H (2013) Higher-order assemblies in a new paradigm of signal transduction. Cell 153(2):287–292. https://doi.org/10.1016/j.cell.2013.03.013
Zhu W, von dem Bussche A, Yi X, Qiu Y, Wang Z, Weston P, Hurt RH, Kane AB, Gao H (2016) Nanomechanical mechanism for lipid bilayer damage induced by carbon nanotubes confined in intracellular vesicles. Proc Natl Acad Sci U S A 113(44):12374–12379
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Cox Jr., L.A., Popken, D.A., Sun, R.X. (2018). Mechanistic Causality: Biological Mechanisms of Dose-Response Thresholds for Inflammation-Mediated Diseases Caused by Asbestos Fibers and Mineral Particles. In: Causal Analytics for Applied Risk Analysis. International Series in Operations Research & Management Science, vol 270. Springer, Cham. https://doi.org/10.1007/978-3-319-78242-3_9
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