Immunomodulatory effects of testosterone and letrozole during Plasmodium berghei ANKA infection

被引:1
作者
Nolasco-Perez, Teresita de Jesus [1 ,2 ]
Cervantes-Candelas, Luis Antonio [1 ]
Buendia-Gonzalez, Fidel Orlando [1 ,2 ]
Aguilar-Castro, Jesus [1 ,2 ]
Fernandez-Rivera, Omar [1 ,2 ]
Salazar-Castanon, Victor Hugo [1 ]
Legorreta-Herrera, Martha [1 ]
机构
[1] Univ Nacl Autonoma Mexico, Div Estudios Posgrad Invest, Unidad Invest Quim Computac Sintesis & Farmacol Mo, Lab Inmunol Mol,Fac Estudios Super Zaragoza, Ciudad De Mexico, Mexico
[2] Univ Nacl Autonoma Mexico, Posgrad Ciencias Biol, Ciudad De Mexico, Mexico
来源
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY | 2023年 / 13卷
关键词
Plasmodium berghei ANKA; malaria; sex hormones; androgen; testosterone; letrozole; immune response; parasite; SEX-HORMONES MODULATE; T-CELLS; CHABAUDI MALARIA; B-CELLS; GLUCOSE-METABOLISM; GAMMA-INTERFERON; IMMUNE-RESPONSE; MICE; PROTECTION; SPLEEN;
D O I
10.3389/fcimb.2023.1146356
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
IntroductionMalaria is one of the leading health problems globally. Plasmodium infection causes pronounced sexual dimorphism, and the lethality and severity are more remarkable in males than in females. To study the role of testosterone in the susceptibility and mortality of males in malaria, it is common to increase its concentration. However, this strategy does not consider the enzyme CYP19A1 aromatase, which can transform it into oestrogens. MethodsTo avoid the interference of oestrogens, we inhibited in vivo CYP19A1 aromatase with letrozole and increased the testosterone level by exogen administration before infection with Plasmodium berghei ANKA. We measured the impact on free testosterone, 17 & beta;-oestradiol and dehydroepiandrosterone levels in plasma; additionally, we evaluated parasitaemia, body temperature, body mass, glucose levels and haemoglobin concentration. Furthermore, we evaluated the effects of testosterone on the immune response; we quantified the CD3+/CD4+, CD3+/CD8+, CD19+, Mac-3+ and NK cells in the spleen and the plasma concentrations of the cytokines IL-2, IL-4, IL-6, IFN-, IL-10, TNF-& alpha; and IL-17A. Finally, we quantified the levels of antibodies. ResultsWe found that mice treated with the combination of letrozole and testosterone and infected with Plasmodium berghei ANKA had increased concentrations of free testosterone and DHEA but decreased levels of 17 & beta;-oestradiol. As a result, parasitaemia increased, leading to severe anaemia. Interestingly, testosterone increased temperature and decreased glucose concentration as a possible testosterone-mediated regulatory mechanism. The severity of symptomatology was related to critical immunomodulatory effects generated by free testosterone; it selectively increased CD3+CD8+ T and CD19+ cells but decreased Mac-3+. Remarkably, it reduced IL-17A concentration and increased IL-4 and TNF-& alpha;. Finally, it increased IgG1 levels and the IgG1/IgG2a ratio. In conclusion, free testosterone plays an essential role in pathogenesis in male mice by increasing CD8+ and decreasing Mac3+ cells and mainly reducing IL-17A levels, which is critical in the development of anaemia. Our results are important for understanding the mechanisms that regulate the exacerbated inflammatory response in infectious diseases and would be useful for the future development of alternative therapies to reduce the mortality generated by inflammatory processes.
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页数:17
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