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GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever

(2018) JOURNAL OF EXPERIMENTAL MEDICINE. 215(6). p.1519-1529
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Abstract
Pyroptosis is an inflammasome-induced lytic cell death mode, the physiological role of which in chronic inflammatory diseases is unknown. Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting an estimated 150,000 patients. The disease is caused by missense mutations in Mefv that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that Clostridium difficile infection of FMF knock-in macrophages that express a chimeric FMF-associated Mefv(V726A) Pyrin elicited pyroptosis and gasdermin D (GSDMD)-mediated interleukin (IL)-1 beta secretion. Importantly, in vivo GSDMD deletion abolished spontaneous autoinflammatory disease. GSDMD-deficient FMF knock-in mice were fully protected from the runted growth, anemia, systemic inflammatory cytokine production, neutrophilia, and tissue damage that characterize this autoinflammatory disease model. Overall, this work identifies pyroptosis as a critical mechanism of IL-1 beta-dependent autoinflammation in FMF and highlights GSDMD inhibition as a potential antiinflammatory strategy in inflammasome-driven diseases.
Keywords
PYRIN INFLAMMASOME ACTIVATION, PYROPTOTIC CELL-DEATH, GASDERMIN D, INTERLEUKIN-1-BETA, SECRETION, DISEASES, CASPASE-11, IL-1-BETA, RELEASE

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MLA
Kanneganti, Apurva et al. “GSDMD Is Critical for Autoinflammatory Pathology in a Mouse Model of Familial Mediterranean Fever.” JOURNAL OF EXPERIMENTAL MEDICINE 215.6 (2018): 1519–1529. Print.
APA
Kanneganti, A., Malireddi, R. S., Viana Saavedra, P. H., Vande Walle, L., Van Gorp, H., Kambara, H., Tillman, H., et al. (2018). GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever. JOURNAL OF EXPERIMENTAL MEDICINE, 215(6), 1519–1529.
Chicago author-date
Kanneganti, Apurva, RK Subbarao Malireddi, Pedro Henrique Viana Saavedra, Lieselotte Vande Walle, Hanne Van Gorp, Hiroto Kambara, Heather Tillman, et al. 2018. “GSDMD Is Critical for Autoinflammatory Pathology in a Mouse Model of Familial Mediterranean Fever.” Journal of Experimental Medicine 215 (6): 1519–1529.
Chicago author-date (all authors)
Kanneganti, Apurva, RK Subbarao Malireddi, Pedro Henrique Viana Saavedra, Lieselotte Vande Walle, Hanne Van Gorp, Hiroto Kambara, Heather Tillman, Peter Vogel, Hongbo R Luo, Ramnik J Xavier, Hongbo Chi, and Mohamed Lamkanfi. 2018. “GSDMD Is Critical for Autoinflammatory Pathology in a Mouse Model of Familial Mediterranean Fever.” Journal of Experimental Medicine 215 (6): 1519–1529.
Vancouver
1.
Kanneganti A, Malireddi RS, Viana Saavedra PH, Vande Walle L, Van Gorp H, Kambara H, et al. GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever. JOURNAL OF EXPERIMENTAL MEDICINE. 2018;215(6):1519–29.
IEEE
[1]
A. Kanneganti et al., “GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever,” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 215, no. 6, pp. 1519–1529, 2018.
@article{8582296,
  abstract     = {Pyroptosis is an inflammasome-induced lytic cell death mode, the physiological role of which in chronic inflammatory diseases is unknown. Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting an estimated 150,000 patients. The disease is caused by missense mutations in Mefv that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that Clostridium difficile infection of FMF knock-in macrophages that express a chimeric FMF-associated Mefv(V726A) Pyrin elicited pyroptosis and gasdermin D (GSDMD)-mediated interleukin (IL)-1 beta secretion. Importantly, in vivo GSDMD deletion abolished spontaneous autoinflammatory disease. GSDMD-deficient FMF knock-in mice were fully protected from the runted growth, anemia, systemic inflammatory cytokine production, neutrophilia, and tissue damage that characterize this autoinflammatory disease model. Overall, this work identifies pyroptosis as a critical mechanism of IL-1 beta-dependent autoinflammation in FMF and highlights GSDMD inhibition as a potential antiinflammatory strategy in inflammasome-driven diseases.},
  author       = {Kanneganti, Apurva and Malireddi, RK Subbarao and Viana Saavedra, Pedro Henrique and Vande Walle, Lieselotte and Van Gorp, Hanne and Kambara, Hiroto and Tillman, Heather and Vogel, Peter and Luo, Hongbo R and Xavier, Ramnik J and Chi, Hongbo and Lamkanfi, Mohamed},
  issn         = {0022-1007},
  journal      = {JOURNAL OF EXPERIMENTAL MEDICINE},
  keywords     = {PYRIN INFLAMMASOME ACTIVATION,PYROPTOTIC CELL-DEATH,GASDERMIN D,INTERLEUKIN-1-BETA,SECRETION,DISEASES,CASPASE-11,IL-1-BETA,RELEASE},
  language     = {eng},
  number       = {6},
  pages        = {1519--1529},
  title        = {GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever},
  url          = {http://dx.doi.org/10.1084/jem.20172060},
  volume       = {215},
  year         = {2018},
}

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