Cystatin C regulates major histocompatibility complex-II-peptide presentation and extracellular signal-regulated kinase-dependent polarizing cytokine production by bone marrow-derived dendritic cells
- Author(s)
- Zhang, W; Zi, M; Sun, L; WANG, F; Chen, S; Zhao, Y; Liang, S; Hu, J; Liu, S; Liu, L; Zhan, Y; Lew, AM; Xu, Y;
- Details
- Publication Year 2019-11,Volume 97,Issue #10,Page 916-930
- Journal Title
- Immunol Cell Biol
- Publication Type
- Journal Article
- Abstract
- Cystatin C is a ubiquitously expressed cysteine protease inhibitor that protects cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases. Although commonly used as a serum biomarker for evaluating renal function, cystatin C is associated with many immunological disorders under various pathophysiological conditions. How cystatin C affects immune cells, especially dendritic cells (DCs), however, is far from clear. In this study, we found that pharmacological treatment with or genetic overexpression of cystatin C in bone marrow-derived DCs (BMDCs) reduced their capacity to stimulate CD4(+) T-cell proliferation, despite increased antigen uptake. This reduced capacity corresponded with reduced major histocompatibility complex-II presentation owing to diminished levels of the chaperon H2-DM in BMDCs. Instead of promoting proliferation, cystatin C promoted skewing of T cells toward proinflammatory T-helper (Th)1/Th17 differentiation. This was mediated by augmented extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase phosphorylation in BMDCs, leading to secretion of polarizing cytokines, which in turn led to the Th deviation. Collectively, our study explained the cellular and molecular basis of how this protease inhibitor can regulate immune responses, namely by affecting BMDCs and their cytokine pathway. Our results might open up an avenue for the development of therapeutic agents for the treatment of cystatin C-related immunological diseases.
- Publisher
- Wiley
- Research Division(s)
- Immunology
- PubMed ID
- 31513306
- Publisher's Version
- https://doi.org/10.1111/imcb.12290
- NHMRC Grants
- NHMRC/1037321, NHMRC/1105209, NHMRC/1143976, NHMRC/1150425, NHMRC/1080321,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-11-20 02:45:24
Last Modified: 2019-11-21 10:26:06