Hydroxychloroquine induces apoptosis of myeloid-derived suppressor cells via up-regulation of CD81 contributing to alleviate lupus symptoms

Abstract

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that results from widespread immune complex deposition and secondary tissue injury. Hydroxychloroquine (HCQ) has been used clinically to treat SLE, while its exact mechanism has still remained elusive. Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of SLE. In this study, we aimed to explore the effects of HCQ on the apoptosis of MDSCs in lupus mice and its possible molecular regulatory mechanism. Methods We constructed the imiquimod (IMQ)-induced lupus model in mice. The proportion and apoptosis of MDSCs were measured by flow cytometry. CD81-overexpressed adeno-associated virus was intraperitoneally injected into the lupus mice. We also transfected the CD81 siRNA into bone marrow-derived MDSCs, and employed qRT-PCR and Western blotting to quantify the level of CD81. Results The results showed that HCQ ameliorated IMQ-induced lupus symptoms, and simultaneously inhibited the expansion of MDSCs. In particular, HCQ induced the apoptosis of MDSCs, and also up-regulated the expression level of CD81 in MDSCs, which might indicate the relationship between the expression level of CD81 and the apoptosis of MDSCs. CD81 was further confirmed to participate in the apoptosis of MDSCs and lupus disease progression by overexpressing CD81 in vivo. Molecular docking experiment further proved the targeting effect of HCQ on CD81. And then we interfered CD81 in bone marrow derived MDSCs in vitro, and it was revealed that HCQ rescued the decreased expression level of CD81 and relieved the immune imbalance of Th17/Treg cells. Conclusion In summary, HCQ promoted the apoptosis of MDSCs by up-regulating the expression level of CD81 in MDSCs, and ultimately alleviated lupus symptoms. Our results may assist scholars to develop further effective therapies for SLE.

The correlation between Th17/Treg immune dysregulation and the disease severity in chronic spontaneous urticaria patients

“…28 Notably, dysregulation of Th17 cells and Treg cells with an increase in Th17 cell populations and a decrease in Treg cell populations has been observed in systemic lupus erythematosus. 29 Our study aligns with these observations, as we identified an elevated proportion of Th17 cells and a reduced proportion of Treg cells in CSU patients. IL-22 and IL-17 are crucial cytokines involved in the immune defense of psoriatic plaques through their ability to facilitate the production of antimicrobial proteins.…”

“… 28 Notably, dysregulation of Th17 cells and Treg cells with an increase in Th17 cell populations and a decrease in Treg cell populations has been observed in systemic lupus erythematosus. 29 Our study aligns with these observations, as we identified an elevated proportion of Th17 cells and a reduced proportion of Treg cells in CSU patients.…”

“…An existing study has demonstrated the activation of Treg cell subpopulations, specifically Foxp3 + T cells, can effectively suppress the activity of Th1 and Th17 cells 28 . Notably, dysregulation of Th17 cells and Treg cells with an increase in Th17 cell populations and a decrease in Treg cell populations has been observed in systemic lupus erythematosus 29 . Our study aligns with these observations, as we identified an elevated proportion of Th17 cells and a reduced proportion of Treg cells in CSU patients.…”

High-dimensional single-cell analysis unveils distinct immune signatures of peripheral blood in patients with pancreatic ductal adenocarcinoma

“…These data indicated that PDAC patients had a higher expression of S100A family members, which was found to be associated with tumor aggressive and metastasis previously ( 28 ). Up-regulation of S100A9 expression inhibited the differentiation of DCs and macrophages and induced accumulation of MDSCs ( 29 ). We found that the proportion of S100A9 + monocytes was significantly up-regulated in PDAC patients compared to the healthy controls ( Figures 6F, G ).…”

Cannabidiol regulates apoptosis and autophagy in inflammation and cancer: A review

“…In patients with SLE, the accumulation of myeloid-derived suppressor cells (MDSCs) is positively correlated to disease activity. Hydroxychloroquine may relieve the symptoms of SLE inflammation by regulating the expression of CD81 in MDSCs and inducing their apoptosis ( Ni et al, 2022 ). Taken together, promoting the apoptosis of key cells in inflammatory diseases and reducing the secretion of inflammatory cytokines are crucial in alleviating inflammatory responses.…”