P063 - INTERACTIONS OF GENETIC AND ENVIRONMENTAL FACTORS TRIGGER UNIQUE PPAR-GAMMA SIGNATURE IN PANETH CELLS IN CROHN'S DISEASE SUBJECTS AND RELEVANT MOUSE MODELS
(Room Poster Hall)
19 Jan 18
5:30 PM
-
7:00 PM
Tracks:
Clinical and Research Challenges
Background: Crohn's disease (CD) pathogenicity involves interplay of genetic and environmental factors (G+E). CD subjects and mice harboring ATG16L1 T300A, a key CD susceptibility allele, showed Paneth cell (PC) defects upon exposure to cigarette smoking, a known CD environmental risk factor. Thus, PC phenotype can integrate G+E effects. RNA-seq of full thickness ileum showed reduced PPAR-γ signaling in T300A-smoked mice. Treatment with the PPAR-γ agonist rosiglitazone rescued PC defects in T300A-smoked mice. However, it was unclear if the G+E effect was mediated through a direct effect on PCs. Methods: Mice were exposed to cigarette smoke (4 cigarettes/day) for 5 days/week for 2 weeks. Microarray data from laser capture microdissected (LCM) PCs from T300A-smoked mice was compared to two other LCM PC datasets: 1) Atg16l1HM mice infected with MNV and 2) CD subjects with ATG16L1 T300A genotype who smoked. PC-specific loss of Atg16l1 expression was achieved by crossing Cryptdin-4-Cre mice with Atg16l1fl/fl to generate Cryptdin-4-Cre/Atg16l1fl/fl (PC-Cre+) mice and Atg16l1fl/fl littermate controls (PC-Cre-). Rosiglitazone was administered by oral gavage at 20 mg/kg/day. Results: LCM PCs from T300A-smoked mice showed significantly diminished expression of many PPAR-γ-associated genes, as compared to controls. Similarly, PPAR-γ-associated genes were enriched among the downregulated genes in Atg16l1HM-MNV infected mice and CD smokers with ATG16L1 T300A. PC defects were observed only in PC-Cre+ mice exposed to cigarette smoking and not in PC-Cre- controls. PC-Cre+ smoked mice also showed increased crypt base apoptosis, similar to T300A-smoked mice. The smoking-induced PC defects and crypt base apoptosis in the PC-Cre+ mice were rescued by rosiglitazone treatment. Conclusion: These data collectively suggest that G+E interplay directly affects PCs. PPAR-γ signaling is a central, mechanistic link between G+E combination and PC defects in CD subjects and relevant mouse models.