Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner
Marianne R. Spalinger, … , Gerhard Rogler, Michael Scharl
Marianne R. Spalinger, … , Gerhard Rogler, Michael Scharl
Published May 20, 2019
Citation Information: J Clin Invest. 2019;129(6):2527-2541. https://doi.org/10.1172/JCI123263.
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Research Article Gastroenterology

Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner

Abstract

The gut microbiota is crucial for our health, and well-balanced interactions between the host’s immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host’s response to the intestinal microbiota.

Authors

Marianne R. Spalinger, Thomas S.B. Schmidt, Marlene Schwarzfischer, Larissa Hering, Kirstin Atrott, Silvia Lang, Claudia Gottier, Annelies Geirnaert, Christophe Lacroix, Xuezhi Dai, David J. Rawlings, Andrew C. Chan, Christian von Mering, Gerhard Rogler, Michael Scharl

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Figure 10

PTPN22 affects expression of antimicrobial peptides in an IL-18–dependent manner.

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PTPN22 affects expression of antimicrobial peptides in an IL-18–dependen...
(A) Reg3g mRNA expression in WT, PTPN22–/–, and 619W mice after the first DSS cycle (day 8), after recovery (day 18), or at the end of chronic colitis induction (day 85). (B) MC-38 cells were grown on inserts and cocultured with MDP-activated bone marrow–derived macrophages (BMDMs) or anti-CD3/CD28–activated T cells from WT, PTPN22–/–, or 619W mice, and mRNA levels of Reg3g were analyzed by quantitative PCR. (C and D) MC-38 cells were cocultured with MDP-activated BMDMs from WT, PTPN22–/–, or 619W mice in the presence of an isotype control or an anti–IL-18 antibody and analyzed for mRNA expression of Reg3g (C) and Defa5 (D). Data are representative of 1 of 2 independent experiments. Depicted are mean values and SEM, and each dot represents 1 individual mouse or experimental sample. *P < 0.05, **P < 0.01, ***P < 0.001, Kruskal-Wallis test.