title: Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation.
abstract: Crohn's disease (CD) is a chronic, immune-mediated, inflammatory disorder of the intestine that has been linked to numerous susceptibility genes, including the immunity-related GTPase (IRG) M (IRGM). IRGs comprise a family of proteins known to confer resistance to intracellular infections through various mechanisms, including regulation of phagosome processing, cell motility, and autophagy. However, despite its association with CD, the role of IRGM and other IRGs in regulating intestinal inflammation is unclear. We investigated the involvement of Irgm1, an ortholog of IRGM, in the genesis of murine intestinal inflammation. After dextran sodium sulfate exposure, Irgm1-deficient [Irgm1 knockout (KO)] mice showed increased acute inflammation in the colon and ileum, with worsened clinical responses. Marked alterations of Paneth cell location and granule morphology were present in Irgm1 KO mice, even without dextran sodium sulfate exposure, and were associated with impaired mitophagy and autophagy in Irgm1 KO intestinal cells (including Paneth cells). This was manifested by frequent tubular and swollen mitochondria and increased LC3-positive autophagic structures. Interestingly, these LC3-positive structures often contained Paneth cell granules. These results suggest that Irgm1 modulates acute inflammatory responses in the mouse intestine, putatively through the regulation of gut autophagic processes, that may be pivotal for proper Paneth cell functioning.
authors.affiliation: PO Box 3003, Duke Univ. Medical Center, Durham, NC 27710. taylo018@mc.duke.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Ajay S
authors.initials: AS
authors.lastname: Gulati
authors.forename: Viviana
authors.initials: V
authors.lastname: Cantillana
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Henry
authors.forename: Elyse A
authors.initials: EA
authors.lastname: Schmidt
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Daniell
authors.forename: Emily
authors.initials: E
authors.lastname: Grossniklaus
authors.forename: Alexi A
authors.initials: AA
authors.lastname: Schoenborn
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001343:Autophagy; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007079:Ileitis / Q000139:chemically induced / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D063306:Mitophagy; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: C096000:Ifi1 protein, mouse; D016264:Dextran Sulfate; D019204:GTP-Binding Proteins
keywords: autophagy; experimental colitis; immunity-related GTPases