Protein inhibitor of activated STAT3 reduces peripheral arthritis and gut inflammation and regulates the Th17/Treg cell imbalance via STAT3 signaling in a mouse model of spondyloarthritis

Hong-Ki Min,Hyun Sik Na,Mi-La Cho,Sung-Hwan Park,Seung-Ki Kwok,Hyeon-Beom Seo,Seon-Yeong Lee,Jun-Geol Ryu,Jeongwon Choi,Kyungah Jung

doi:10.1186/s12967-019-1774-x

Hong-Ki Min, Hyun Sik Na + Show 8 more

Open Access

https://doi.org/10.1186/s12967-019-1774-x

Copy DOI

Abstract

BackgroundSpondyloarthritis (SpA) is chronic inflammatory arthritis, and interleukin (IL)-17 is crucial in SpA pathogenesis. Type 17 helper T (Th17) cells are one of major IL-17-secreting cells. Signal transducer and activator of transcription (STAT)-3 signaling induces Th17 differentiation. This study investigated the effects of protein inhibitor of activated STAT3 (PIAS3) on SpA pathogenesis. Curdlan was injected into SKG ZAP-70W163C mice for SpA induction.MethodsThe PIAS3 or Mock vector was inserted into mice for 10 weeks. Clinical and histologic scores of the paw, spine, and gut were evaluated. The expression of IL-17, tumor necrosis factor-α (TNF-α), STAT3, and bone morphogenic protein (BMP) was measured. Confocal microscopy and flow cytometry were used to assess Th cell differentiation.ResultsPIAS3 significantly diminished the histologic scores of the paw and gut. PIAS3-treated mice displayed decreased expression of IL-17, TNF-α, and STAT3 in the paw, spine, and gut. BMP-2/4 expression was lower in the spines of PIAS3-treated mice. Th cell differentiation was polarized toward the upregulation of regulatory T cells (Tregs) and the downregulation of Th17 in PIAS3-treated mice.ConclusionPIAS3 had beneficial effects in mice with SpA by reducing peripheral arthritis and gut inflammation. Pro-inflammatory cytokines and Th17/Treg differentiation were controlled by PIAS3. In addition, BMPs were decreased in the spines of PIAS3-treated mice. These findings suggest that PIAS3 could have therapeutic benefits in patients with SpA.

Highlights

Spondyloarthritis (SpA) is chronic inflammatory arthritis, and interleukin (IL)-17 is crucial in SpA pathogenesis
Beneficial effects of PIAS on peripheral arthritis in mice with SpA The clinical and histologic scores of peripheral arthritis were assessed to determine the preventive effects of protein inhibitor of activated STAT3 (PIAS3) on SpA mice
The arthritis score of PIAS3-treated mice was significantly lower than that of Mock-treated mice, and a gross histology image revealed that the joint structure of PIAS3-treated mice was more preserved than that of Mock-treated mice (Fig. 1b)

Summary

Introduction

Spondyloarthritis (SpA) is chronic inflammatory arthritis, and interleukin (IL)-17 is crucial in SpA pathogenesis. Type 17 helper T (Th17) cells are one of major IL-17-secreting cells. This study investigated the effects of protein inhibitor of activated STAT3 (PIAS3) on SpA pathogenesis. Interleukin (IL)-17 is a key pathologic cytokine in SpA pathogenesis, and various immune cells such as type 17 helper T (Th17) cells, natural killer T (NKT) cells, and γδ T cells secrete IL-17 [1]. Th17 cells are a major source of IL-17, and an increased number of circulating Th17 cells was discovered in SpA patients [6, 7]. In contrast to IL-17-secreting cells, regulatory T cells (Tregs) maintain self-tolerance and play a suppressive role in autoimmune diseases [8]. An imbalance in Th17 cells and Tregs is observed in SpA, and research studies have shown that potential therapeutic agents can ameliorate SpA symptoms by regulating the Th17/Treg cell imbalance [11, 12]

Methods

Results

Discussion

Conclusion