Vitronectin-derived bioactive peptide prevents spondyloarthritis by modulating Th17/Treg imbalance in mice with curdlan-induced spondyloarthritis

Hong Ki Min,Jeongwon Choi,A Ram Lee,Mi-La Cho,Seon-Yeong Lee,Byung-Moo Min,Sung-Hwan Park,Yeonseok Chung

doi:10.1371/journal.pone.0262183

Hong Ki Min, Jeongwon Choi + Show 6 more

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https://doi.org/10.1371/journal.pone.0262183

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Abstract

Spondyloarthritis (SpA) is a systemic inflammatory arthritis mediated mainly by interleukin (IL)-17. The vitronectin-derived bioactive peptide, VnP-16, exerts an anti-osteoporotic effect via β1 and αvβ3 integrin signaling. SpA is associated with an increased risk of osteoporosis, and we investigated the effect of VnP-16 in mice with SpA. SpA was induced by curdlan in SKG ZAP-70W163C mice, which were treated with vehicle, celecoxib, VnP-16, or VnP-16+celecoxib. The clinical score, arthritis score, spondylitis score, and proinflammatory cytokine expression of the spine were evaluated by immunohistochemical staining. Type 17 helper T cell (Th17) and regulatory T cell (Treg) differentiation in the spleen was evaluated by flow cytometry and in the spine by confocal staining. Splenocyte expression of signal transducer and activator of transcription (STAT) 3 and pSTAT3 was evaluated by in vitro Western blotting. The clinical score was significantly reduced in the VnP16+celecoxib group. The arthritis and spondylitis scores were significantly lower in the VnP-16 and VnP16+celecoxib groups than the vehicle group. In the spine, the levels of IL-1β, IL-6, tumor necrosis factor-α, and IL-17 expression were reduced and Th17/Treg imbalance was regulated in the VnP-16 alone and VnP-16+celecoxib groups. Flow cytometry of splenocytes showed increased polarization of Tregs in the VnP-16+celecoxib group. In vitro, VnP-16 suppressed pSTAT3. VnP-16 plus celecoxib prevented SpA progression in a mouse model by regulating the Th17/Treg imbalance and suppressing the expression of proinflammatory cytokines.

Highlights

Spondyloarthritis (SpA) is an inflammatory arthritis, which affects about 0.20 to 1.61% of the population [1]
The arthritis and spondylitis scores were significantly lower in the VnP-16 and VnP16+celecoxib groups than the vehicle group
We reported that modulation of the Th17/Treg imbalance and suppression of pro-inflammatory cytokines by signal transducer and activator of transcription (STAT) 3 inhibitors, rebamipide and protein inhibitor of activated STAT3, prevented axial SpA (axSpA) in mice [9, 10]

Summary

Introduction

Spondyloarthritis (SpA) is an inflammatory arthritis, which affects about 0.20 to 1.61% of the population [1]. SpA has two subtypes: axial SpA (axSpA) and peripheral SpA [2]. The treatment of axSpA aims to reduce the inflammatory response and suppress abnormal bony bridging of axial joints [3]. The treatment guidelines for axSpA recommend non-steroidal anti-inflammatory drugs (NSAIDs) as the first-line therapy for patients with axSpA and active arthritis symptoms [4]. Th17 cells are upregulated in the peripheral blood of patients with axSpA [7]. The circulating Th17 level and regulatory T cell (Treg) abundance are positively and negatively, respectively, correlated with axSpA disease activity [8]. We reported that modulation of the Th17/Treg imbalance and suppression of pro-inflammatory cytokines by signal transducer and activator of transcription (STAT) 3 inhibitors, rebamipide and protein inhibitor of activated STAT3, prevented axSpA in mice [9, 10]

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