Stanniocalcin-2 contributes to mesenchymal stromal cells attenuating murine contact hypersensitivity mainly via reducing CD8+ Tc1 cells

Xiaoyong Chen,Xiaoran Zhang,Wenjie Xia,Chang Liu,Andy Peng Xiang,Li Huang,Qiuli Liu,Yan Xu,Yanwen Peng,Chuang Cai,Gang Li,Jiancheng Wang,Shuwei Zheng,Weijun Huang,Qi Zhang

doi:10.1038/s41419-018-0614-x

Abstract

Mesenchymal stromal cells (MSCs) have been demonstrated to ameliorate allergic contact dermatitis (ACD), a typical T-cell-mediated disorder. However, the underlying mechanisms behind the MSC-based treatment for ACD have not yet been fully elucidated. The stanniocalcins (STCs) comprise a family of secreted glycoprotein hormones that act as important anti-inflammatory proteins. Here, we investigated the roles of STCs in MSC-mediated T-cell suppression and their potential role in the MSC-based treatment for ACD. Gene expression profiling revealed that STC2, but not STC1, was highly expressed in MSCs. STC2 knockdown in MSCs significantly impaired their effects in reducing TNF-α- and IFN-γ-producing CD8+ T cells. Importantly, silencing the STC2 expression in MSCs abated their therapeutic effect on contact hypersensitivity (CHS) in mice, mainly restoring the generation and infiltration of IFN-γ-producing CD8+ T cells (Tc1 cells). Mechanistically, STC2 co-localized with heme oxygenase 1 (HO-1) in MSCs, and contributed to MSC-mediated reduction of CD8+ Tc1 cells via regulating HO-1 activity. Together, these findings newly identify STC2 as the first stanniocalcin responsible for mediating the immunomodulatory effects of MSCs on allogeneic T cells and STC2 contribute to MSC-based treatment for ACD mainly via reducing the CD8+ Tc1 cells.

Highlights

Allergic contact dermatitis (ACD) is an inflammatory skin condition manifest as an allergic response caused by contact with immune-stimulating substances
Our results showed that STC2 was highly expressed in human Mesenchymal stromal cells (MSCs), whereas STC1 showed relatively low-level expression (Fig. 1a)
Due to the relatively abundant expression of STC2 in MSCs, we investigated the potential involvement of STC2 in mediating the immunomodulatory effect of MSCs on allogeneic T cells

Summary

Introduction

Allergic contact dermatitis (ACD) is an inflammatory skin condition manifest as an allergic response caused by contact with immune-stimulating substances. Mesenchymal stromal cells (MSCs), a multipotent stromal cell subset that can differentiate into osteoblasts, adipocytes, and chondrocytes[9], have shown promise in preclinical and clinical therapies for a variety of T-cellmediated diseases, largely due to their immunomodulatory effects on T cells. Official journal of the Cell Death Differentiation Association. Chen et al Cell Death and Disease (2018)9:548 activation, inhibit T-cell proliferation, and reduce their secretions of pro-inflammatory cytokines[10,11]. MSCs reportedly inhibit both CD4+ T helper (Th) cells and CD8+ cytotoxic T lymphocytes via direct and/or indirect actions[12]. Recent preclinical and clinical studies demonstrated that MSCs are becoming a promising therapeutic option for ACD13,14. The underlying mechanisms behind the MSC-based treatment for ACD have not yet been fully elucidated

Methods

Results

Conclusion