FASEB JOURNAL
·
2024
·Vol. 38
·期 23
·e70211
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IF 4.4
Lengshan Mo,Cansheng Hong,Zhihan Jiang,Yiqiang Zhu,Lu Zhou,Simin Tan,Guorong Deng,Yanwei Qi,Tengfei Hu,Qianlian Wu,Yi Zhao,Huaina Qiu,Taizhen Liang,Peibin Lin,Jian Zhang,Xiancai Ma,Quan Yang
Malaria remains a significant global public health problem. T follicular helper (Tfh) cells, a subset of CD4 + T cells, have the capacity to regulate B cells, plasma cells, and antibody production, among other functions. Myeloid-derived suppressor cells (MDSCs) possess strong immunosuppressive abilities and can negatively regulate various immune responses. However, the role of MDSCs in inhibiting Tfh-cell responses during Plasmodium infection remains unclear. In this study, we investigated the regulatory effect of MDSCs on Tfh cell-mediated immune responses upon Plasmodium infection. We found that the numbers of MDSCs increased upon Plasmodium infection. Further mechanism study revealed that MDSC-derived Arg-1 and PD-L1 prevented Tfh cell proliferation and activation. Conversely, the addition of nor-NOHA or anti-PD-L1 monoclonal antibodies enhanced the proliferation and activation of Tfh cells, indicating that the inhibitory effect of MDSCs on Tfh cells was dependent on Arg-1 and PD-1/PD-L1. In vivo depletion of MDSCs enhanced Tfh-cell responses and antibody production, as well as relieved symptoms of infected mice and improved their survival rates. These findings provide insights into the immunosuppressive role of MDSCs in inhibiting Tfh cell immune responses and further impairing humoral immunity. Our study provides new strategies for malaria prevention and control.
研究领域:
免疫学
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寄生虫学
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感染性疾病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
·
2024
·
IF 3.6
Zhu Yiqiang,Zhou Lu,Mo Lengshan,Hong Cansheng,Pan Lingxia,Lin Jie,Qi Yanwei,Tan Simin,Qian Manhongtian,Hu Tengfei,Zhao Yi,Qiu Huaina,Lin Peibin,Ma Xiancai,Yang Quan
Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii–infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti–Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii–infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria.
研究领域:
免疫学
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传染病学
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细胞生物学
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疟疾
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产品关联
DOI
PubMed
高影响因子
PARASITOLOGY RESEARCH
·
2021
·Vol. 120
·期 8
·2827-2837
·
IF 2.289
Guo Wenju,Li Ning,Ren Guolian,Wang RongRong,Chai Liqing,Li Yujie,Wang Xi,Yang Qingshan,Wang Ruili,Zhang Guoshun,Yang Liuqing,Yi Bofang,Zhang Shuqiu
Currently, conjugation of artemisinin-derived dimers, trimers, and tetramers is a viable strategy for developing new effective antimalarial candidates. Furthermore, nanotechnology is an effective means to achieve intravenous administration of hydrophobic drugs. In this paper, an ester-linked dihydroartemisinin trimer (DHA 3 ) was synthesized and further prepared as self-assembled nanoparticles (DHA 3 NPs) by a one-step nanoprecipitation method. The pharmacokinetics and antimalarial pharmacodynamics of DHA 3 NPs were studied in rats and mice infected with Plasmodium yoelii BY265 (PyBY265) . DHA 3 NPs had a regular spherical shape with a uniform size distribution of 140.27 ± 3.59 nm, entrapment efficiency (EE) of 99.63 ± 0.17%, and drug loading efficiency (DL) of 79.62 ± 0.11%. The in vitro release characterization revealed that DHA 3 NPs were easily hydrolysed into DHA in an esterase environment. The pharmacokinetics study demonstrated that the area under the concentration–time curve ( AUC 0-t ) of DHA in DHA 3 NPs group was 2070.52 ± 578.76 h×ng×mL −1 , which was higher than that of DHA and artesunate (AS) control groups ( AUC 0-t values of 724.18 ± 94.32 and 448.40 ± 94.45 h×ng×mL −1 , respectively) ( P < 0.05). The antimalarial pharmacodynamics in vivo suggested that DHA 3 NP S (ED 90 7.82 ± 1.16 μmol×(kg×day) −1 ) had a superior antimalarial effect compared with that of control groups (ED 90 values of 14.68 ± 0.98 (DHA) and 14.34 ± 1.96 (AS) μmol×(kg×day) −1 ) ( P < 0.05). In addition, DHA 3 NP S reduced the recurrence ratio and improved the cure ratio and survival time. In summary, DHA 3 NPs exhibited promising pharmacokinetic characteristics and antimalarial pharmacodynamics in vivo.
研究领域:
药理学
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纳米技术
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疟疾研究
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产品关联
DOI
PubMed
高影响因子
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