遺伝子欠損が炎症性腸疾患の抗菌防御力を弱めることがマウス実験で判明 Gene loss weakens antibacterial defense in inflammatory bowel disease in mouse study
PTPN2はマウスにおける回腸パネス細胞の生存率と機能の重要なレギュレーターである PTPN2 is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice
Vinicius Canale,Marianne R. Spalinger,Rocio Alvarez,Anica Sayoc-Becerra,Golshid Sanati,Salomon Manz,Pritha Chatterjee,Alina N. Santos,Hillmin Lei,Sharon Jahng,Timothy Chu,Ali Shawki,Elaine Hanson,Lars Eckmann,André J. Ouellette,Declan F. McCole
Cellular and Molecular Gastroenterology and Hepatology
Published:April 06, 2023
Background & Aims
Loss-of-function variants in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene are associated with increased risk of Inflammatory Bowel Disease (IBD). We recently showed that Ptpn2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC-macrophage communication, and modulation of the gut microbiome in mice restricting expansion of a small intestinal pathobiont associated with IBD. Here, we aimed to identify how Ptpn2-loss affects ileal IEC subtypes and their function in vivo.
Constitutive Ptpn2-wild-type (WT), heterozygous (HET) and knockout (KO) mice, as well as mice with inducible deletion of Ptpn2 in IECs, were used in the study. Investigation was performed using imaging techniques, flow cytometry, enteroid culture, and analysis of gene and protein levels of IEC markers.
Partial transcriptome analysis revealed that Paneth cell-associated antimicrobial peptides (AMP) Lyz1, Pla2g2a and Defa6 expression, were markedly downregulated in Ptpn2-KO mice compared with WT and HET. In parallel, Paneth cell numbers were reduced, their endoplasmic reticulum (ER) architecture was disrupted, and the ER stress protein, CHOP, was increased in Ptpn2-KO mice. Despite reduced Paneth cell number, flow cytometry showed increased expression of the Paneth cell-stimulatory cytokines IL-22 and IFN-γ+ in CD4+ T-cells isolated from Ptpn2-KO ileum. Key findings in constitutive Ptpn2-KO mice were confirmed in epithelium-specific Ptpn2ΔIEC mice, which also showed impaired lysozyme protein levels in Paneth cells compared to Ptpn2fl/fl control mice.
Constitutive Ptpn2-deficiency affects Paneth cell viability and compromises Paneth cell-specific AMP production. The observed effects may contribute to the increased susceptibility to intestinal infection and dysbiosis in these mice.