The NLRP3 Inflammasome Protects against Loss of Epithelial Integrity and Mortality during Experimental Colitis

Md Hasan Zaki, Kelli L. Boyd, Peter Vogel, Michael B. Kastan, Mohamed Lamkanfi, Thirumala Devi Kanneganti

Research output: Contribution to journalArticle

500 Citations (Scopus)

Abstract

Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1β (IL-1β) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.

Original languageEnglish (US)
Pages (from-to)379-391
Number of pages13
JournalImmunity
Volume32
Issue number3
DOIs
StatePublished - Mar 2010

Fingerprint

Inflammasomes
Colitis
Caspase 1
Interleukin-18
Mortality
Dextran Sulfate
Proteins
Interleukin-1
Chemokines
Crohn Disease
Colon
Leukocytes
Homeostasis
Maintenance
Bacteria

Keywords

  • Cellimmuno
  • Molimmuno

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

The NLRP3 Inflammasome Protects against Loss of Epithelial Integrity and Mortality during Experimental Colitis. / Zaki, Md Hasan; Boyd, Kelli L.; Vogel, Peter; Kastan, Michael B.; Lamkanfi, Mohamed; Kanneganti, Thirumala Devi.

In: Immunity, Vol. 32, No. 3, 03.2010, p. 379-391.

Research output: Contribution to journalArticle

Zaki, Md Hasan ; Boyd, Kelli L. ; Vogel, Peter ; Kastan, Michael B. ; Lamkanfi, Mohamed ; Kanneganti, Thirumala Devi. / The NLRP3 Inflammasome Protects against Loss of Epithelial Integrity and Mortality during Experimental Colitis. In: Immunity. 2010 ; Vol. 32, No. 3. pp. 379-391.
@article{00c8625632d541728cef3b1dadf45fcf,
title = "The NLRP3 Inflammasome Protects against Loss of Epithelial Integrity and Mortality during Experimental Colitis",
abstract = "Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1β (IL-1β) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.",
keywords = "Cellimmuno, Molimmuno",
author = "Zaki, {Md Hasan} and Boyd, {Kelli L.} and Peter Vogel and Kastan, {Michael B.} and Mohamed Lamkanfi and Kanneganti, {Thirumala Devi}",
year = "2010",
month = "3",
doi = "10.1016/j.immuni.2010.03.003",
language = "English (US)",
volume = "32",
pages = "379--391",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - The NLRP3 Inflammasome Protects against Loss of Epithelial Integrity and Mortality during Experimental Colitis

AU - Zaki, Md Hasan

AU - Boyd, Kelli L.

AU - Vogel, Peter

AU - Kastan, Michael B.

AU - Lamkanfi, Mohamed

AU - Kanneganti, Thirumala Devi

PY - 2010/3

Y1 - 2010/3

N2 - Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1β (IL-1β) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.

AB - Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1β (IL-1β) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.

KW - Cellimmuno

KW - Molimmuno

UR - http://www.scopus.com/inward/record.url?scp=77950002937&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950002937&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2010.03.003

DO - 10.1016/j.immuni.2010.03.003

M3 - Article

VL - 32

SP - 379

EP - 391

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 3

ER -