Trichosanthin alleviates streptozotocin-induced type 1 diabetes mellitus in mice by regulating the balance between bone marrow-derived IL6+ and IL10+ MDSCs

Jie Shu; Kefan Wang; Yuting Liu; Jie Zhang; Xuping Ding; Hanxiao Sun; Jiaoxiang Wu; Biao Huang; Ju Qiu; Huiming Sheng; Liming Lu

doi:10.1016/j.heliyon.2023.e22907

Trichosanthin alleviates streptozotocin-induced type 1 diabetes mellitus in mice by regulating the balance between bone marrow-derived IL6⁺ and IL10⁺ MDSCs

Heliyon. 2023 Dec 12;10(1):e22907. doi: 10.1016/j.heliyon.2023.e22907. eCollection 2024 Jan 15.

Authors

Jie Shu^{1

2}, Kefan Wang², Yuting Liu², Jie Zhang², Xuping Ding², Hanxiao Sun¹, Jiaoxiang Wu¹, Biao Huang³, Ju Qiu⁴, Huiming Sheng¹, Liming Lu²

Affiliations

¹ Department of Clinical Laboratory, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai, 200336, China.
² Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 Chong Qing South Road, 200025, China.
³ College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
⁴ The Key Laboratory of Stem Cell Biology, Shanghai Institutes of Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Abstract

Myeloid-derived suppressor cells (MDSCs) occupy a pivotal role in the intricate pathogenesis of the autoimmune disorder, Type 1 diabetes mellitus (T1DM). Since our previous work demonstrated that trichosanthin (TCS), an active compound of Chinese herb medicine Tian Hua Fen, regulated immune response, we aimed to clarify the efficacy and molecular mechanism of TCS in the treatment of T1DM. To this end, T1DM mouse model was established by streptozotocin (STZ) induction. The mice were randomly divided into normal control group (Ctl), T1DM group (STZ), TCS treated diabetic group (STZ + TCS) and insulin-treated diabetic group (STZ + insulin). Our comprehensive evaluation encompassed variables such as blood glucose, glycosylated hemoglobin, body weight, pertinent biochemical markers, pancreatic histopathology, and the distribution of immune cell populations. Furthermore, we meticulously isolated MDSCs from the bone marrow of T1DM mice, probing into the expressions of genes pertaining to the advanced glycation end product receptor (RAGE)/NF-κB signaling pathway through RT-qPCR. Evidently, TCS exhibited a substantial capacity to effectively counteract the T1DM-induced elevation in random blood glucose, glycosylated hemoglobin, and IL-6 levels in plasma. Pathological scrutiny underscored the ability of TCS to mitigate the damage incurred by islets. Intriguingly, TCS interventions engendered a reduction in the proportion of MDSCs within the bone marrow, particularly within the IL-6⁺ MDSC subset. In contrast, IL-10⁺ MDSCs exhibited an elevation following TCS treatment. Moreover, we observed a significant down-regulation of relative mRNA of pro-inflammatory genes, including arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), RAGE and NF-κB, within MDSCs due to the influence of TCS. It decreases total MDSCs and regulates the balance between IL-6⁺ and IL-10⁺ MDSCs thus alleviating the symptoms of T1DM. TCS also down-regulates the RAGE/NF-κB signaling pathway, making it a promising alternative therapeutic treatment for T1DM. Collectively, our study offered novel insights into the underlying mechanism by which TCS serves as a promising therapeutic intervention for T1DM.

Keywords: Advanced glycation end product receptor; Myeloid-derived suppressor cells; Tian hua fen; Trichosanthin(TCS); Type 1 diabetes mellitus.