PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis
Wan-Chen Hsieh, … , Stephanie M. Stanford, Nunzio Bottini
Wan-Chen Hsieh, … , Stephanie M. Stanford, Nunzio Bottini
Published October 15, 2020
Citation Information: JCI Insight. 2020;5(20):e141868. https://doi.org/10.1172/jci.insight.141868.
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Research Article Inflammation

PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis

Abstract

Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 (PTPN2) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2-haploinsufficient SKG mice — modeling human carriers of disease-associated variants of PTPN2 — displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) — a gut-enriched Treg subset that can undergo conversion into FoxP3–IL-17+ arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2. Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein–coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15+ Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15+ exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs.

Authors

Wan-Chen Hsieh, Mattias N.D. Svensson, Martina Zoccheddu, Michael L. Tremblay, Shimon Sakaguchi, Stephanie M. Stanford, Nunzio Bottini

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Figure 6

Inducible Treg-specific Ptpn2 haploinsufficiency aggravates development of DSS-induced arthritis.

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Inducible Treg-specific Ptpn2 haploinsufficiency aggravates development ...
(A) Schematic of B6.SKG.H2d/d FoxP3EGFP-ERT2-Cre+/+ tdTomatofl/fl Ptpn2+/+ or Ptpn2fl/+ inducible Treg fate-mapping mice. (B–G) Female Ptpn2+/+ (n = 5) and Ptpn2fl/+ (n = 7) inducible Treg fate-mapping mice received 0.5% DSS in their drinking water for 10 days. After 10 days, the water was replaced with regular drinking water until the end of the experiment at day 61. Treg fate-mapping mice were administered 100 μL tamoxifen (20 mg/mL) via oral gavage for 5 consecutive days to induce Cre expression. After the last treatment with tamoxifen, mice were rested for 2 weeks before receiving DSS drinking water. (B) Change in body weight. (C) Clinical score and change in ankle thickness. (D) Number of IL-17–producing exTregs (CD4+tdTomato+IL-17A+FoxP3–) in lymph nodes, ankles, and colons. (E and F) Number of IL-17–producing (E) GPR15+ or (F) GPR15– exTregs (CD4+tdTomato+IL-17A+FoxP3–) in lymph nodes, ankles, and colons. (G) Number of tdTomato– Th17 (CD4+tdTomato–IL-17A+FoxP3–) in lymph nodes, ankles, and colons. Compiled data from 2 independent experiments are shown. Clinical score and ankle swelling were quantified using the area under the curve. Each symbol in D–G represents an individual mouse. Graphs show mean ± SEM *P < 0.05, **P < 0.01, ***P < 0.001 by Mann-Whitney U test (C) or unpaired t test (D–G).