Increased expression of TLR2 in CD4(+) T cells from SLE patients enhances immune reactivity and promotes IL-17 expression through histone modifications

Yu Liu; Jieyue Liao; Ming Zhao; Haijing Wu; Susan Yung; Tak Mao Chan; Akihiko Yoshimura; Qianjin Lu

doi:10.1002/eji.201445219

Increased expression of TLR2 in CD4(+) T cells from SLE patients enhances immune reactivity and promotes IL-17 expression through histone modifications

Eur J Immunol. 2015 Sep;45(9):2683-93. doi: 10.1002/eji.201445219. Epub 2015 Jun 26.

Authors

Yu Liu¹, Jieyue Liao¹, Ming Zhao¹, Haijing Wu¹, Susan Yung², Tak Mao Chan², Akihiko Yoshimura³, Qianjin Lu¹

Affiliations

¹ Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, P. R. China.
² Division of Nephrology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
³ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.

PMID: 26079624
DOI: 10.1002/eji.201445219

Abstract

The innate immune system has been shown to play an important pathologic role in systemic lupus erythematosus (SLE). TLR2, a PRR, recognizes exogenous PAMPs, and endogenous damage-associated molecular patterns and has been implicated in the initiation and maintenance of the perpetuated inflammatory reactions in autoimmune diseases. Here, we report increased expression of TLR2 in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes from SLE patients. Conventional treatment, such as hydroxychloroquine and corticosteroids, showed no effect on TLR2 expression in CD4(+) T cells from SLE patients. In vitro stimulation of TLR2 in CD4(+) T cells from SLE patients increased CD40L and CD70 expression, as well as secretion of IL-6, IL-17A, IL-17F, and TNF-α, while Foxp3 transcription decreased. This effect was reversed by TLR2 siRNA. Moreover, TLR2 activation upregulated H3K4 tri-methylation and H4 acetylation levels while downregulated H3K9 tri-methylation level in the IL-17A promoter region. In addition, it also increased H4 acetylation levels and decreased H3K9 tri-methylation levels in the IL-17F promoter region. In summary, our findings demonstrate that increased expression of TLR2 contributes to immune reactivity and promotes IL-17A and IL-17F expression through histone modifications in SLE.

Keywords: Histone modification; IL-17; Systemic lupus erythematosus; T cells; TLR2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
B-Lymphocytes / pathology
CD27 Ligand / genetics
CD27 Ligand / immunology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism*
CD4-Positive T-Lymphocytes / pathology
CD40 Ligand / genetics
CD40 Ligand / immunology
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / pathology
DNA Methylation
Epigenesis, Genetic / immunology*
Female
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / immunology
Histones / genetics
Histones / immunology
Histones / metabolism*
Humans
Immunity, Innate
Interleukin-17 / genetics*
Interleukin-17 / immunology
Lupus Erythematosus, Systemic / genetics*
Lupus Erythematosus, Systemic / immunology
Lupus Erythematosus, Systemic / metabolism
Lupus Erythematosus, Systemic / pathology
Male
Middle Aged
Primary Cell Culture
Promoter Regions, Genetic
RNA, Small Interfering / genetics
RNA, Small Interfering / immunology
Signal Transduction
Toll-Like Receptor 2 / antagonists & inhibitors
Toll-Like Receptor 2 / genetics*
Toll-Like Receptor 2 / immunology

Substances

CD27 Ligand
CD70 protein, human
FOXP3 protein, human
Forkhead Transcription Factors
Histones
IL17A protein, human
IL17F protein, human
Interleukin-17
RNA, Small Interfering
TLR2 protein, human
Toll-Like Receptor 2
CD40 Ligand