publication . Article . Other literature type . 2019

ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis

Scambler, Thomas; Jarosz-Griffiths, Heledd H; Lara-Reyna, Samuel; Pathak, Shelly; Wong, Chi; Holbrook, Jonathan; Martinon, Fabio; Savic, Sinisa; Peckham, Daniel; McDermott, Michael F;
Open Access English
  • Published: 18 Sep 2019 Journal: eLife, volume 8 (eissn: 2050-084X, Copyright policy)
  • Publisher: eLife Sciences Publications, Ltd
  • Country: United Kingdom
Abstract
Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 ...
Subjects
free text keywords: Cell Line; Cystic Fibrosis/pathology; Epithelial Sodium Channels/metabolism; Humans; Immunity, Innate; Inflammation/pathology; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; Sodium/metabolism; NLRP3; autoinflammation; cystic fibrosis; human; human biology; immunology; inflammasome; inflammation; medicine; potassium transport; sodium transport, Research Article, Human Biology and Medicine, Immunology and Inflammation, inflammasome, cystic fibrosis, sodium transport, potassium transport, autoinflammation, NLRP3, Human, General Biochemistry, Genetics and Molecular Biology, General Immunology and Microbiology, General Neuroscience, General Medicine, Downregulation and upregulation, Bicarbonate transport, Inflammation, medicine.symptom, medicine, Epithelial sodium channel, medicine.drug, Biology, Cystic fibrosis transmembrane conductance regulator, biology.protein, Cell biology, medicine.disease, Proinflammatory cytokine
Funded by
WT
Project
  • Funder: Wellcome Trust (WT)
74 references, page 1 of 5

Aksentijevich, I, Masters, SL, Ferguson, PJ, Dancey, P, Frenkel, J, van Royen-Kerkhoff, A, Laxer, R, Tedgård, U, Cowen, EW, Pham, TH, Booty, M, Estes, JD, Sandler, NG, Plass, N, Stone, DL, Turner, ML, Hill, S, Butman, JA, Schneider, R, Babyn, P, El-Shanti, HI, Pope, E, Barron, K, Bing, X, Laurence, A, Lee, CC, Chapelle, D, Clarke, GI, Ohson, K, Nicholson, M, Gadina, M, Yang, B, Korman, BD, Gregersen, PK, van Hagen, PM, Hak, AE, Huizing, M, Rahman, P, Douek, DC, Remmers, EF, Kastner, DL, Goldbach-Mansky, R. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. New England Journal of Medicine. 2009; 360: 2426-2437 [OpenAIRE] [PubMed] [DOI]

Allen, IC, TeKippe, EM, Woodford, RM, Uronis, JM, Holl, EK, Rogers, AB, Herfarth, HH, Jobin, C, Ting, JP. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated Cancer. The Journal of Experimental Medicine. 2010; 207: 1045-1056 [OpenAIRE] [PubMed] [DOI]

Althaus, M. ENaC inhibitors and airway re-hydration in cystic fibrosis: state of the art. Current Molecular Pharmacology. 2013; 6: 3-12 [OpenAIRE] [PubMed] [DOI]

Bals, R, Weiner, DJ, Wilson, JM. The innate immune system in cystic fibrosis lung disease. Journal of Clinical Investigation. 1999; 103: 303-307 [OpenAIRE] [PubMed] [DOI]

Berdiev, BK, Qadri, YJ, Benos, DJ. Assessment of the CFTR and ENaC association. Mol. BioSyst.. 2009; 5: 123-127 [OpenAIRE] [PubMed] [DOI]

Bergsbaken, T, Fink, SL, Cookson, BT. Pyroptosis: host cell death and inflammation. Nature Reviews Microbiology. 2009; 7: 99-109 [OpenAIRE] [PubMed] [DOI]

Boucher, RC. Muco-Obstructive lung diseases. New England Journal of Medicine. 2019; 380: 1941-1953 [PubMed] [DOI]

Cookson, BT, Brennan, MA. Pro-inflammatory programmed cell death. Trends in Microbiology. 2001; 9: 113-114 [OpenAIRE] [PubMed] [DOI]

Drug developement pipeline. 2017

del Campo, R, Martínez, E, del Fresno, C, Alenda, R, Gómez-Piña, V, Fernández-Ruíz, I, Siliceo, M, Jurado, T, Toledano, V, Arnalich, F, García-Río, F, López-Collazo, E. Translocated LPS Might Cause Endotoxin Tolerance in Circulating Monocytes of Cystic Fibrosis Patients. PLOS ONE. 2011; 6 [OpenAIRE] [PubMed] [DOI]

del Fresno, C, Gómez-Piña, V, Lores, V, Soares-Schanoski, A, Fernández-Ruiz, I, Rojo, B, Alvarez-Sala, R, Caballero-Garrido, E, García, F, Veliz, T, Arnalich, F, Fuentes-Prior, P, García-Río, F, López-Collazo, E. Monocytes from Cystic Fibrosis Patients Are Locked in an LPS Tolerance State: Down-Regulation of TREM-1 as Putative Underlying Mechanism. PLOS ONE. 2008; 3 [OpenAIRE] [PubMed] [DOI]

del Fresno, C, García-Rio, F, Gómez-Piña, V, Soares-Schanoski, A, Fernández-Ruíz, I, Jurado, T, Kajiji, T, Shu, C, Marín, E, Gutierrez del Arroyo, A, Prados, C, Arnalich, F, Fuentes-Prior, P, Biswas, SK, López-Collazo, E. Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients. The Journal of Immunology. 2009; 182: 6494-6507 [OpenAIRE] [PubMed] [DOI]

Di, A, Xiong, S, Ye, Z, Malireddi, RKS, Kometani, S, Zhong, M, Mittal, M, Hong, Z, Kanneganti, T-D, Rehman, J, Malik, AB. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 Inflammasome-Induced inflammation. Immunity. 2018; 49: 56-65 [OpenAIRE] [PubMed] [DOI]

Domingo-Fernández, R, Coll, RC, Kearney, J, Breit, S, O'Neill, LAJ. The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome. Journal of Biological Chemistry. 2017; 292: 12077-12087 [OpenAIRE] [PubMed] [DOI]

Donaldson, SH, Boucher, RC. Sodium channels and cystic fibrosis. Chest. 2007; 132: 1631-1636 [OpenAIRE] [PubMed] [DOI]

74 references, page 1 of 5
Abstract
Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 ...
Subjects
free text keywords: Cell Line; Cystic Fibrosis/pathology; Epithelial Sodium Channels/metabolism; Humans; Immunity, Innate; Inflammation/pathology; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; Sodium/metabolism; NLRP3; autoinflammation; cystic fibrosis; human; human biology; immunology; inflammasome; inflammation; medicine; potassium transport; sodium transport, Research Article, Human Biology and Medicine, Immunology and Inflammation, inflammasome, cystic fibrosis, sodium transport, potassium transport, autoinflammation, NLRP3, Human, General Biochemistry, Genetics and Molecular Biology, General Immunology and Microbiology, General Neuroscience, General Medicine, Downregulation and upregulation, Bicarbonate transport, Inflammation, medicine.symptom, medicine, Epithelial sodium channel, medicine.drug, Biology, Cystic fibrosis transmembrane conductance regulator, biology.protein, Cell biology, medicine.disease, Proinflammatory cytokine
Funded by
WT
Project
  • Funder: Wellcome Trust (WT)
74 references, page 1 of 5

Aksentijevich, I, Masters, SL, Ferguson, PJ, Dancey, P, Frenkel, J, van Royen-Kerkhoff, A, Laxer, R, Tedgård, U, Cowen, EW, Pham, TH, Booty, M, Estes, JD, Sandler, NG, Plass, N, Stone, DL, Turner, ML, Hill, S, Butman, JA, Schneider, R, Babyn, P, El-Shanti, HI, Pope, E, Barron, K, Bing, X, Laurence, A, Lee, CC, Chapelle, D, Clarke, GI, Ohson, K, Nicholson, M, Gadina, M, Yang, B, Korman, BD, Gregersen, PK, van Hagen, PM, Hak, AE, Huizing, M, Rahman, P, Douek, DC, Remmers, EF, Kastner, DL, Goldbach-Mansky, R. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. New England Journal of Medicine. 2009; 360: 2426-2437 [OpenAIRE] [PubMed] [DOI]

Allen, IC, TeKippe, EM, Woodford, RM, Uronis, JM, Holl, EK, Rogers, AB, Herfarth, HH, Jobin, C, Ting, JP. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated Cancer. The Journal of Experimental Medicine. 2010; 207: 1045-1056 [OpenAIRE] [PubMed] [DOI]

Althaus, M. ENaC inhibitors and airway re-hydration in cystic fibrosis: state of the art. Current Molecular Pharmacology. 2013; 6: 3-12 [OpenAIRE] [PubMed] [DOI]

Bals, R, Weiner, DJ, Wilson, JM. The innate immune system in cystic fibrosis lung disease. Journal of Clinical Investigation. 1999; 103: 303-307 [OpenAIRE] [PubMed] [DOI]

Berdiev, BK, Qadri, YJ, Benos, DJ. Assessment of the CFTR and ENaC association. Mol. BioSyst.. 2009; 5: 123-127 [OpenAIRE] [PubMed] [DOI]

Bergsbaken, T, Fink, SL, Cookson, BT. Pyroptosis: host cell death and inflammation. Nature Reviews Microbiology. 2009; 7: 99-109 [OpenAIRE] [PubMed] [DOI]

Boucher, RC. Muco-Obstructive lung diseases. New England Journal of Medicine. 2019; 380: 1941-1953 [PubMed] [DOI]

Cookson, BT, Brennan, MA. Pro-inflammatory programmed cell death. Trends in Microbiology. 2001; 9: 113-114 [OpenAIRE] [PubMed] [DOI]

Drug developement pipeline. 2017

del Campo, R, Martínez, E, del Fresno, C, Alenda, R, Gómez-Piña, V, Fernández-Ruíz, I, Siliceo, M, Jurado, T, Toledano, V, Arnalich, F, García-Río, F, López-Collazo, E. Translocated LPS Might Cause Endotoxin Tolerance in Circulating Monocytes of Cystic Fibrosis Patients. PLOS ONE. 2011; 6 [OpenAIRE] [PubMed] [DOI]

del Fresno, C, Gómez-Piña, V, Lores, V, Soares-Schanoski, A, Fernández-Ruiz, I, Rojo, B, Alvarez-Sala, R, Caballero-Garrido, E, García, F, Veliz, T, Arnalich, F, Fuentes-Prior, P, García-Río, F, López-Collazo, E. Monocytes from Cystic Fibrosis Patients Are Locked in an LPS Tolerance State: Down-Regulation of TREM-1 as Putative Underlying Mechanism. PLOS ONE. 2008; 3 [OpenAIRE] [PubMed] [DOI]

del Fresno, C, García-Rio, F, Gómez-Piña, V, Soares-Schanoski, A, Fernández-Ruíz, I, Jurado, T, Kajiji, T, Shu, C, Marín, E, Gutierrez del Arroyo, A, Prados, C, Arnalich, F, Fuentes-Prior, P, Biswas, SK, López-Collazo, E. Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients. The Journal of Immunology. 2009; 182: 6494-6507 [OpenAIRE] [PubMed] [DOI]

Di, A, Xiong, S, Ye, Z, Malireddi, RKS, Kometani, S, Zhong, M, Mittal, M, Hong, Z, Kanneganti, T-D, Rehman, J, Malik, AB. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 Inflammasome-Induced inflammation. Immunity. 2018; 49: 56-65 [OpenAIRE] [PubMed] [DOI]

Domingo-Fernández, R, Coll, RC, Kearney, J, Breit, S, O'Neill, LAJ. The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome. Journal of Biological Chemistry. 2017; 292: 12077-12087 [OpenAIRE] [PubMed] [DOI]

Donaldson, SH, Boucher, RC. Sodium channels and cystic fibrosis. Chest. 2007; 132: 1631-1636 [OpenAIRE] [PubMed] [DOI]

74 references, page 1 of 5
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publication . Article . Other literature type . 2019

ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis

Scambler, Thomas; Jarosz-Griffiths, Heledd H; Lara-Reyna, Samuel; Pathak, Shelly; Wong, Chi; Holbrook, Jonathan; Martinon, Fabio; Savic, Sinisa; Peckham, Daniel; McDermott, Michael F;