The DNA Sensor AIM2 Maintains Intestinal Homeostasis via Regulation of Epithelial Antimicrobial Host Defense

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50 Citations (Scopus)

Abstract

Microbial pattern molecules in the intestine play immunoregulatory roles via diverse pattern recognition receptors. However, the role of the cytosolic DNA sensor AIM2 in the maintenance of intestinal homeostasis is unknown. Here, we show that Aim2 -/- mice are highly susceptible to dextran sodium sulfate-induced colitis that is associated with microbial dysbiosis as represented by higher colonic burden of commensal Escherichia coli. Colonization of germ-free mice with Aim2 -/- mouse microbiota leads to higher colitis susceptibility. In-depth investigation of AIM2-mediated host defense responses reveals that caspase-1 activation and IL-1β and IL-18 production are compromised in Aim2 -/- mouse colons, consistent with defective inflammasome function. Moreover, IL-18 infusion reduces E.coli burden as well as colitis susceptibility in Aim2 -/- mice. Altered microbiota in inflammasome-defective mice correlate with reduced expression of several antimicrobial peptides in intestinal epithelial cells. Together, these findings implicate DNA sensing by AIM2 as a regulatory mechanism for maintaining intestinal homeostasis. AIM2 is a cytosolic DNA sensor. Hu etal. demonstrate that intestinal microbial DNA activates the AIM2 inflammasome. AIM2 activation leads to the production of IL-1β and IL-18, which participate in the regulation of intestinal microbiota such as Escherichia coli via induction of the antimicrobial peptides in intestinal epithelial cells.

Original languageEnglish (US)
JournalCell Reports
DOIs
StateAccepted/In press - Apr 3 2015

Fingerprint

Inflammasomes
Interleukin-18
Homeostasis
Escherichia coli
DNA
Sensors
Colitis
Interleukin-1
Chemical activation
Microbiota
Pattern Recognition Receptors
Caspase 1
Dextran Sulfate
Peptides
Epithelial Cells
Dysbiosis
Molecules
Intestines
Colon
Maintenance

Keywords

  • AIM2
  • Antimicrobial peptides
  • Colitis
  • DNA sensor
  • Escherichia coli
  • Inflammasome
  • Inflammation
  • Inflammatory bowel diseases
  • Intestinal epithelium
  • Pattern recognition receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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title = "The DNA Sensor AIM2 Maintains Intestinal Homeostasis via Regulation of Epithelial Antimicrobial Host Defense",
abstract = "Microbial pattern molecules in the intestine play immunoregulatory roles via diverse pattern recognition receptors. However, the role of the cytosolic DNA sensor AIM2 in the maintenance of intestinal homeostasis is unknown. Here, we show that Aim2 -/- mice are highly susceptible to dextran sodium sulfate-induced colitis that is associated with microbial dysbiosis as represented by higher colonic burden of commensal Escherichia coli. Colonization of germ-free mice with Aim2 -/- mouse microbiota leads to higher colitis susceptibility. In-depth investigation of AIM2-mediated host defense responses reveals that caspase-1 activation and IL-1β and IL-18 production are compromised in Aim2 -/- mouse colons, consistent with defective inflammasome function. Moreover, IL-18 infusion reduces E.coli burden as well as colitis susceptibility in Aim2 -/- mice. Altered microbiota in inflammasome-defective mice correlate with reduced expression of several antimicrobial peptides in intestinal epithelial cells. Together, these findings implicate DNA sensing by AIM2 as a regulatory mechanism for maintaining intestinal homeostasis. AIM2 is a cytosolic DNA sensor. Hu etal. demonstrate that intestinal microbial DNA activates the AIM2 inflammasome. AIM2 activation leads to the production of IL-1β and IL-18, which participate in the regulation of intestinal microbiota such as Escherichia coli via induction of the antimicrobial peptides in intestinal epithelial cells.",
keywords = "AIM2, Antimicrobial peptides, Colitis, DNA sensor, Escherichia coli, Inflammasome, Inflammation, Inflammatory bowel diseases, Intestinal epithelium, Pattern recognition receptors",
author = "Shuiqing Hu and Lan Peng and Kwak, {Youn Tae} and Tekippe, {Erin McElvania} and Chandrashekhar Pasare and Malter, {James S.} and Hooper, {Lora V.} and Zaki, {Md Hasan}",
year = "2015",
month = "4",
day = "3",
doi = "10.1016/j.celrep.2015.10.040",
language = "English (US)",
journal = "Cell Reports",
issn = "2211-1247",
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TY - JOUR

T1 - The DNA Sensor AIM2 Maintains Intestinal Homeostasis via Regulation of Epithelial Antimicrobial Host Defense

AU - Hu, Shuiqing

AU - Peng, Lan

AU - Kwak, Youn Tae

AU - Tekippe, Erin McElvania

AU - Pasare, Chandrashekhar

AU - Malter, James S.

AU - Hooper, Lora V.

AU - Zaki, Md Hasan

PY - 2015/4/3

Y1 - 2015/4/3

N2 - Microbial pattern molecules in the intestine play immunoregulatory roles via diverse pattern recognition receptors. However, the role of the cytosolic DNA sensor AIM2 in the maintenance of intestinal homeostasis is unknown. Here, we show that Aim2 -/- mice are highly susceptible to dextran sodium sulfate-induced colitis that is associated with microbial dysbiosis as represented by higher colonic burden of commensal Escherichia coli. Colonization of germ-free mice with Aim2 -/- mouse microbiota leads to higher colitis susceptibility. In-depth investigation of AIM2-mediated host defense responses reveals that caspase-1 activation and IL-1β and IL-18 production are compromised in Aim2 -/- mouse colons, consistent with defective inflammasome function. Moreover, IL-18 infusion reduces E.coli burden as well as colitis susceptibility in Aim2 -/- mice. Altered microbiota in inflammasome-defective mice correlate with reduced expression of several antimicrobial peptides in intestinal epithelial cells. Together, these findings implicate DNA sensing by AIM2 as a regulatory mechanism for maintaining intestinal homeostasis. AIM2 is a cytosolic DNA sensor. Hu etal. demonstrate that intestinal microbial DNA activates the AIM2 inflammasome. AIM2 activation leads to the production of IL-1β and IL-18, which participate in the regulation of intestinal microbiota such as Escherichia coli via induction of the antimicrobial peptides in intestinal epithelial cells.

AB - Microbial pattern molecules in the intestine play immunoregulatory roles via diverse pattern recognition receptors. However, the role of the cytosolic DNA sensor AIM2 in the maintenance of intestinal homeostasis is unknown. Here, we show that Aim2 -/- mice are highly susceptible to dextran sodium sulfate-induced colitis that is associated with microbial dysbiosis as represented by higher colonic burden of commensal Escherichia coli. Colonization of germ-free mice with Aim2 -/- mouse microbiota leads to higher colitis susceptibility. In-depth investigation of AIM2-mediated host defense responses reveals that caspase-1 activation and IL-1β and IL-18 production are compromised in Aim2 -/- mouse colons, consistent with defective inflammasome function. Moreover, IL-18 infusion reduces E.coli burden as well as colitis susceptibility in Aim2 -/- mice. Altered microbiota in inflammasome-defective mice correlate with reduced expression of several antimicrobial peptides in intestinal epithelial cells. Together, these findings implicate DNA sensing by AIM2 as a regulatory mechanism for maintaining intestinal homeostasis. AIM2 is a cytosolic DNA sensor. Hu etal. demonstrate that intestinal microbial DNA activates the AIM2 inflammasome. AIM2 activation leads to the production of IL-1β and IL-18, which participate in the regulation of intestinal microbiota such as Escherichia coli via induction of the antimicrobial peptides in intestinal epithelial cells.

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KW - Intestinal epithelium

KW - Pattern recognition receptors

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