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

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 r IL-17 r Systemic lupus erythematosus r T cells r TLR2 IntroductionSystemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease that results in multiple organ damage and diverse clinical manifestations [1]. SLE is characterized by T-cell hyperactivity and B-cell overstimulation. Uncontrolled T-cell activation results in increased secretion of inflammatory cytokines, production of autoantibodies, and aberrant inflamCorrespondence: Prof. Qianjin Lu e-mail: qianlu5860@gmail.com matory response, which contribute to the development of SLE [2]. How T cells become hyperactive during SLE remains to be determined. However, both genetic background and environmental factors are believed to contribute to the development of SLE [3]. A number of epidemiological studies have suggested that onset and flares of SLE are associated with infection [4]. One of the mechanisms whereby invasive microorganisms disrupt host immune system is through the interaction with TLRs, as demonstrated in experimental lupus [5,6]. * These authors contributed equally to this work. Eur. J. Immunol. 2015. 45: 2683-2693 TLRs are membrane-bound proteins referred to as pathogenassociated molecular patterns that belong to innate immune system. Each TLR can recognize a specific set of microbes bearing PAMPs and endogenous damage-associated molecular patterns (DAMPs) [7]. Activation of TLRs can trigger intracellularsignaling cascades and upregulate the expression of inflammatory cytokines [8]. TLR2 is a cell-surface TLR with extracellular recognition domain that can bind with exogenous ligands including lipoproteins, peptidoglycan, lipoteichoic acid, and endogenous DAMPs, such as HSP70 and high mobility group box protei...

T cells in Systemic Lupus Erythematosus

“…2). Stimulation of SLE T cells through TLR2, a molecule increased in SLE CD4 T cells upon activation of the Syk pathway [28], leads to chromatin opening at the promoters of IL-17A and IL-17F through increased histone acetylation and reduced DNA methylation [29], and activates NF-κB [30]. The protein phosphatase (PP) 2A is increased in SLE T cells; it also controls the IL-17 promoter, inducing hypomethylation by suppressing the DNA methyltransferase 1 pathway, promoting acetylation of histone 3 [31,32], and facilitating the binding of IRF4 which is activated by Rho-associated protein kinase (ROCK)[33].…”

IL-17A levels in systemic lupus erythematosus associated with inflammatory markers and lower rates of malignancy and heart damage: Evidence for a dual role

“…Interleukin 17A is a multifunctional cytokine that impacts neutrophil recruitment, mediating both T-helper-1 (Th1) and T-helper-2 (Th2) cytokine production, and it possesses angiogenic properties through apoptosis modulation (3,12,13). IL-17A production, in vivo and in vitro, is primarily controlled by transforming growth factor beta 1 (TGF-β1) and interleukin 6 (IL-6) via the activation of signal transducer and activator of transcription 3 (STAT-3) in mouse and human models, respectively (14)(15)(16).…”

Association of long non‑coding RNA GAS5 and miR‑21 levels in CD4+ T cells with clinical features of systemic lupus erythematosus

“…The interaction between certain genetic and environmental factors, including chemical factors, viruses and drugs, damages normal immune tolerance and contributes to SLE. Dysfunctional T cells interact with new antigens constantly, leading to a persistent autoimmune reaction (4,5). Previous studies have confirmed that the abnormal activation and proliferation of self-reactive cluster of differentiation (CD)4 + T lymphocytes have a central role in SLE.…”