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.
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shuiqing
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Youn-Tae
authors.initials: YT
authors.lastname: Kwak
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Children's Medical Center, Dallas, TX 75390, USA.
authors.forename: Erin McElvania
authors.initials: EM
authors.lastname: Tekippe
authors.affiliation: Department of Immunology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Pasare
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
authors.affiliation: Department of Immunology, UT Southwestern Medical Center, Dallas, TX 75390, USA; The Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lora V
authors.initials: LV
authors.lastname: Hooper
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hasan.zaki@utsouthwestern.edu.
authors.forename: Md Hasan
authors.initials: MH
authors.lastname: Zaki
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000382:microbiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004198:Disease Susceptibility; D064806:Dysbiosis; D004926:Escherichia coli / Q000472:pathogenicity; D005243:Feces / Q000382:microbiology; D058847:Inflammasomes / Q000378:metabolism; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C540422:Aim2 protein, mouse; D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D004247:DNA; D016264:Dextran Sulfate; D020170:Caspase 1
keywords: AIM2; DNA sensor; Escherichia coli; antimicrobial peptides; colitis; inflammasome; inflammation; inflammatory bowel diseases; intestinal epithelium; pattern recognition receptors