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 3

Ptpn2 haploinsufficiency enhances susceptibility to DSS-induced arthritis in SKG mice.

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Ptpn2 haploinsufficiency enhances susceptibility to DSS-induced arthrit...
(A) Left: Female Ptpn2+/+ (n = 7) and Ptpn2+/– (n = 6) SKG mice received 0.5% DSS in their drinking water for 10 days, after which the water was replaced with regular drinking water until the end of the experiment. Middle: representative colon H&E staining. Right: colon lymphocyte infiltration score. Scale bars: 200 μm. (B) Change in body weight of Ptpn2+/+ (n = 13) and Ptpn2+/– (n = 12) SKG mice receiving 0.5% DSS in their drinking water as described in A. Body weight was measured twice per week. (C) Clinical score and change in ankle thickness of Ptpn2+/+ (n = 13) and Ptpn2+/– (n = 12) SKG mice receiving 0.5% DSS in their drinking water as described in A. (D) Left: representative H&E and toluidine blue staining of arthritic ankles. Right: scores of synovial inflammation, cartilage depletion, and bone erosions. Scale bars: 500 μm. (E and F) Female Ptpn2+/+ and Ptpn2+/– SKG mice received 0.5% DSS drinking water as in A and were sacrificed at 10 days (n = 7 Ptpn2+/+ and n = 8 Ptpn2+/– mice) or 28 days (n = 10 Ptpn2+/+ and n = 10 Ptpn2+/– mice). Number of (E) RORγt+ Tregs (CD4+FoxP3+RORγt+) and (F) Th17 (CD4+IL-17A+FoxP3–) in lymph nodes and ankles. Compiled data from 6 (A–F) independent experiments are shown. Each symbol in A and D–F represents an individual mouse. Arthritis severity was quantified using the area under the curve. Graphs show mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by Mann-Whitney U test (C) or unpaired t test (A and D) or 2-way ANOVA (E and F).