PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis
Wan-Chen Hsieh, Mattias N.D. Svensson, Martina Zoccheddu, Michael L. Tremblay, Shimon Sakaguchi, Stephanie M. Stanford, Nunzio Bottini
Wan-Chen Hsieh, Mattias N.D. Svensson, Martina Zoccheddu, Michael L. Tremblay, Shimon Sakaguchi, Stephanie M. Stanford, Nunzio Bottini
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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 2

Colonic CD4+ T cells promote susceptibility to DSS-induced arthritis in SKG mice.

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Colonic CD4+ T cells promote susceptibility to DSS-induced arthritis in ...
(A) Female SKG mice received 0.5% DSS in their drinking water or regular drinking water (n = 5 mice/group) for 10 days, after which the water was replaced with regular drinking water until the end of the experiment. Arthritis was assessed by clinical scoring and measuring ankle thickness. Body weight was assessed twice per week. (B) Left: representative colon H&E staining. Right: colon lymphocyte infiltration score. Scale bars: 200 μm. (C) Change in body weight of mice in A. (D) Clinical score and change in ankle thickness of mice in A. (E) Numbers of RORγt+ Tregs (CD4+FoxP3+RORγt+) and RORγt+FoxP3–CD4+ T cells in lymph nodes of mice in A. (F) Adoptive transfer of colonic CD4+ T cells (cCD4+) isolated from mice receiving either 0.5% DSS water or regular water for 10 days into Rag2-KO recipient mice. Arthritis was induced 1 week after cell transfer by an intraperitoneal injection of mannan. (G) Clinical score and change in ankle thickness of mice in F receiving cCD4+ T cells from SKG mice treated with either 0.5% DSS water (n = 4) or regular water (n = 5). (H) Flow cytometric analysis of RORγt+ Tregs (CD4+FoxP3+RORγt+) cells in lymph nodes and ankles of arthritic Rag2-KO mice in G. Compiled data from 2 independent experiments are shown in A–E. Each symbol in B, E, and H 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 (D and G) or unpaired t test (B, E, and H).