FGL1-LAG3 axis impairs IL-10-Producing regulatory T cells associated with Systemic lupus erythematosus disease activity
Kang Chen,
Xingyu Li,
Yuqi Shang,
Daxiang Chen,
Siying Qu,
Jinxian Shu,
Mei Zhang,
Zhiying Wang,
Jinmei Huang,
Minhao Wu,
Siqi Ming,
Yongjian Wu
Affiliations
Kang Chen
Department of Laboratory Medicine, Zhongshan City People's Hospital, Zhongshan, Guangdong Province, 528403, China
Xingyu Li
Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Zhuhai, Guangdong Province, 519015, China
Yuqi Shang
Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
Daxiang Chen
Department of Laboratory Medicine, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510091, China
Siying Qu
Department of Clinical Laboratory, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, The Second People's Hospital of Zhuhai, Zhuhai, Guangdong, 519020, China
Jinxian Shu
Department of pharmacy, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China
Mei Zhang
The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong Province, 511518, China
Zhiying Wang
Department of Laboratory Medicine, Zhongshan City People's Hospital, Zhongshan, Guangdong Province, 528403, China
Jinmei Huang
Department of Laboratory Medicine, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510091, China; Corresponding author.
Minhao Wu
Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Corresponding author.
Siqi Ming
Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Zhuhai, Guangdong Province, 519015, China; Corresponding author.
Yongjian Wu
Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Corresponding author.
Background: Systemic Lupus Erythematosus (SLE) is a prototypic autoimmune disease, which is accompanied by liver damage. However, it remains unknown whether liver damage is associated with SLE progression. Method: ology: HepG2 and L-02 cells were stimulated with cytokines, and FGL1 mRNA and protein expression levels were determined using Real-time PCR and ELISA, respectively. Regulatory T cells (Treg) isolated from healthy individuals as well as patients with SLE and SLE and liver damage (SLE-LD) were cultured with autologous effector CD4+T cells in the presence of a functional antibody or isotype control. The expression levels of LAG3, CD25, PD-1, CXCR5, ICOS and OX40 were evaluated by flow cytometry. FGL1, IL-10, IL-17a and IL-21 levels in serum or culture supernatants were quantified by ELISA. Results: Patients with SLE-LD exhibits higher disease activity indices and anti-dsDNA antibody levels. Importantly, fibrinogen-like protein 1 (FGL1), a key factor released from the injured liver, is up-regulated in patients with SLE-LD and is associated with disease activity. FGL1 expression is induced by the inflammatory cytokine IL-6 signaling in hepatocytes. Higher expression of the FGL1 receptor lymphocyte activation gene 3 (LAG3) is detected in Treg cells from patients with SLE-LD. The FGL1-LAG3 signaling axis inhibits Treg cell proliferation and impairs the suppressive activity of Treg cells by limiting IL-10 secretion. Furthermore, FGL1-LAG3 signaling promotes the production of pathogenic IL-17a and IL-21 by CD4+T cells by reducing IL-10 level produced by Treg in patients with SLE. Conclusions: The FGL1-LAG3 signal axis is a key mechanism that subverts the suppressive function of Treg cells. This may provide a new therapeutic target for SLE and SLE-induced liver damage.
