Introduction :
Systemic lupus erythematosus (SLE) is a complex autoimmune disease
manifested by the damage of multiple organs and
systems[11[]
Relle, Manfred et al. “Epigenetic Aspects of Systemic Lupus
Erythematosus.” Rheumatology and therapy vol. 2,1 (2015): 33-46.
doi:10.1007/s40744-015-0014-y]. The pathogenesis
of SLE is characterized by the abnormal activation of T and B
lymphocytes, and the formation of
autoantibodies[22[] Lou, Hantao et al.
“Autoantibodies in systemic lupus erythematosus: From immunopathology
to therapeutic target.” Journal of autoimmunity vol. 132 (2022):
102861. doi:10.1016/j.jaut.2022.102861].
Among which, the imbalance between
regulatory T (Treg) cells and follicular helper T (Tfh) cells has
attracted much attention[33[] He, Jing
et al. “Low-dose interleukin-2 treatment selectively modulates CD4(+)
T cell subsets in patients with systemic lupus erythematosus.” Nature
medicine vol. 22,9 (2016): 991-3. doi:10.1038/nm.4148].
Tfh cells represent a distinct
subset of CD4+ T cells specialized in providing help to B cells and are
required for the formation of germinal centers. In lupus, abnormal
proliferation and function of Tfh cells will lead to pathological
processes like autoantibody production and tissue damage, and thus
become a promising therapeutic target [44[]
Feng, Xuebing et al. “Inhibition of aberrant circulating Tfh cell
proportions by corticosteroids in patients with systemic lupus
erythematosus.” PloS one vol. 7,12 (2012): e51982.
doi:10.1371/journal.pone.0051982][55[]
Wei, Xindi, and Xiaoyin Niu. “T follicular helper cells in autoimmune
diseases.” Journal of autoimmunity vol. 134 (2023): 102976.
doi:10.1016/j.jaut.2022.102976].
Our previous studies have shown that MSCs could suppress Tfh cell
differentiation and proliferation, which was mediated by inducible
nitric oxide synthase (iNOS) [6]. Recently, it has
been proven that bone marrow-derived mesenchymal stem cells (MSCs) from
SLE patients were inefficient to maintain Treg and Tfh balance, while
transplantation of healthy MSCs effectively inhibited the expansion of
Tfh cells and alleviate lupus
symptoms[66[]
Zhang, Zhuoya et al. “Human Umbilical Cord Mesenchymal Stem Cells
Inhibit T Follicular Helper Cell Expansion Through the Activation of
iNOS in Lupus-Prone B6.MRL-Fas Mice.” Cell transplantation vol. 26,6
(2017): 1031-1042. doi:10.3727/096368917X694660][77[]
Jang, Eunkyeong et al. “Infusion of Human Bone Marrow-Derived
Mesenchymal Stem Cells Alleviates Autoimmune Nephritis in a Lupus
Model by Suppressing Follicular Helper T-Cell Development.” Cell
transplantation vol. 25,1 (2016): 1-15. doi:10.3727/096368915X688173].
However, this treatment is only effective for a subset of
patients[88[]
Wang, Dandan et al. “A Long-Term Follow-Up Study of Allogeneic
Mesenchymal Stem/Stromal Cell Transplantation in Patients with
Drug-Resistant Systemic Lupus Erythematosus.” Stem cell reports vol.
10,3 (2018): 933-941. doi:10.1016/j.stemcr.2018.01.029],
for reasons that may be related to the insufficient inhibitory effect or
short persistence time[99[] Nie M, Chen
G, Zhao C, Gan J, Alip M, Zhao Y, Sun L.
Bio-inspired adhesive porous
particles with human MSCs encapsulation for systemic lupus
erythematosus treatment. Bioact Mater. 2020 Aug 10;6(1):84-90. ].
Therefore, it is necessary to find effective strategies to maximize the
therapeutic effect of MSCs.
Silybin (SBI), a flavonoid extracted
from the seeds and fruits of silymarin in the
compositae[1010[] Křen V, Valentová K.
Silybin and its congeners: from traditional medicine to molecular
effects. Nat Prod Rep. 2022 Jun 22;39(6):1264-1281. doi:
10.1039/d2np00013j.], is mainly used as a
liver-protective drug in clinical
practice[1111[] ederico, Alessandro et al.
“Evaluation of the Effect Derived from Silybin with Vitamin D and
Vitamin E Administration on Clinical, Metabolic, Endothelial
Dysfunction, Oxidative Stress Parameters, and Serological Worsening
Markers in Nonalcoholic Fatty Liver Disease Patients.” Oxidative
medicine and cellular longevity vol. 2019 8742075. 15 Oct. 2019,
doi:10.1155/2019/8742075], while studies have
shown it has anti-tumor and
anti-diabetic
effects[1212[] Wei, Zibo et al. “Silybin
suppresses ovarian cancer cell proliferation by inhibiting isocitrate
dehydrogenase 1 activity.” Cancer science vol. 113,9 (2022):
3032-3043. doi:10.1111/cas.15470][1313[]
Liu, Panwen et al. “Silibinin ameliorates STZ-induced impairment of
memory and learning by up- regulating insulin signaling pathway and
attenuating apoptosis.” Physiology & behavior vol. 213 (2020):
112689. doi:10.1016/j.physbeh.2019.112689].
Recently, evidence has suggested that SBI has a therapeutic effect on
collagen-induced arthritis models and patients with rheumatoid
arthritis[1414[] Tong, W W et al.
“Silibinin alleviates inflammation and induces apoptosis in human
rheumatoid arthritis fibroblast-like synoviocytes and has a
therapeutic effect on arthritis in rats.” Scientific reports vol. 8,1
3241. 19 Feb. 2018, doi:10.1038/s41598-018-21674-6][1515[]
Xie, Ying et al. “Suppression of up-regulated LXRα by silybin
ameliorates experimental rheumatoid arthritis and abnormal lipid
metabolism.” Phytomedicine : international journal of phytotherapy
and phytopharmacology vol. 80 (2021): 153339.
doi:10.1016/j.phymed.2020.153339], which opens
new perspectives for the treatment of systemic autoimmune diseases.
Moreover, SBI could up-regulate the gene expression of MSC-related
markers in a pulmonary arterial hypertension rat
model[1616[] Zhang, Tingting et al.
“Silibinin Upregulates CXCR4 Expression in Cultured Bone Marrow Cells
(BMCs) Especially in Pulmonary Arterial Hypertension Rat
Model.” Cells vol. 9,5 1276. 21 May. 2020, doi:10.3390/cells9051276],
suggesting that it may also have an impact on the function of MSCs.
In this study, we systematically
observed the efficacy of SBI alone and in combination with MSCs in the
treatment of lupus mice for the first time and elaborated its regulatory
mechanisms on Tfh cells.