Tissue-specific KO mouse

Case study

Model for Crohn’s disease (CD)

Tschurtschenthaler M, et al. Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. J Exp Med. 2017.

ATG16L1^T300A, a major risk polymorphism in CD, causes impaired autophagy, but it has remained unclear how this predisposes to CD.

Model: Mice that lack Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1^ΔIEC) phenocopying ileal CD observed in humans homozygous for ATG16L1^T300A.

Aim: Investigation of the mechanisms engaged by impaired ATG16L1-dependent autophagy that drive ileal inflammation.

Results: Defective autophagy in IECs predispose to CD ileitis via impaired clearance of endoplasmic reticulum (ER) stress sensor IRE1α aggregates during ER stress.
IRE1α accumulates in Paneth cells, specialized IECs, of Atg16l1^ΔIEC mice, and humans homozygous for ATG16L1^T300A exhibit a corresponding increase of IRE1α in intestinal epithelial crypts.

Figure 1. 35-week-old Atg16l1^ΔIEC mice exhibit increased ER stress and transmural CD-like ileitis.

A-B) Representative H&E images (B) and enteritis histology score (C) of 35-week-old Atg16l1^ΔIEC mice.

Figure 2. IRE1α expression is increased in 35-week-old Atg16l1^ΔIEC mice and ATG16L1^T300A patients and drives CD-like ileitis.

A) Representative confocal images of IRE1α immunoreactivity (green; white arrows) in 10- and 35-week-old Atg16l1^ΔIEC mice.

B) Representative IRE1α immunoreactivity (green) stratified by the ATG16L1 risk allele (AA/AG/GG; A, healthy allele; G risk allele) in healthy controls (n = 9/22/12) and noninflamed mucosa (n = 9/15/7) of CD patients.

C) Quantification of IRE1α+ crypts shown in B in healthy controls (n = 9/22/12) and CD patients (n = 9/15/7) according to their ATG16L1 genotype (n = 18/37/19).