Sex-Associated Differential mRNA Expression of Cytokines and Its Regulation by Sex Steroids in Different Brain Regions in a<i>Plasmodium berghei</i>ANKA Model of Cerebral Malaria

Legorreta-Herrera, Martha; Nava-Castro, Karen Elizabeth; Palacios-Arreola, Margarita Isabel; Hernández-Cervantes, Rosalía; Aguilar-Castro, Jesús; Cervantes-Candelas, Luis Antonio; Morales‐Montor, Jorge

doi:10.1155/2018/5258797

Cited by 4 publications

(3 citation statements)

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“…Immune cells modulate immunity by secreting cytokines. In this work, we detected that infection with P. berghei ANKA increased the concentrations of IFN-γ and TNF-α, which corroborates what has been previously described [ 55 ]. In addition, DHEA administration decreased the concentration of IFN-γ in intact infected females compared to intact infected males, resulting in a sex-associated pattern.…”

Section: Discussionsupporting

confidence: 92%

DHEA Induces Sex-Associated Differential Patterns in Cytokine and Antibody Levels in Mice Infected with Plasmodium berghei ANKA

Buendía-González

Cervantes-Candelas

Aguilar-Castro

et al. 2023

IJMS

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Malaria is the most lethal parasitic disease worldwide; the severity of symptoms and mortality are higher in men than in women, exhibiting an evident sexual dimorphism in the immune response; therefore, the contribution of 17β-estradiol and testosterone to this phenomenon has been studied. Both hormones differentially affect several aspects of innate and adaptive immunity. Dehydroepiandrosterone (DHEA) is the precursor of both hormones and is the sexual steroid in higher concentrations in humans, with immunomodulatory properties in different parasitic diseases; however, the involvement of DHEA in this sexual dimorphism has not been studied. In the case of malaria, the only information is that higher levels of DHEA are associated with reduced Plasmodium falciparum parasitemia. Therefore, this work aims to analyze the DHEA contribution to the sexual dimorphism of the immune response in malaria. We assessed the effect of modifying the concentration of DHEA on parasitemia, the number of immune cells in the spleen, cytokines, and antibody levels in plasma of CBA/Ca mice infected with Plasmodium berghei ANKA (P. berghei ANKA). DHEA differentially affected the immune response in males and females: it decreased IFN-γ, IL-2 and IL-4 concentrations only in females, whereas in gonadectomized males, it increased IgG2a and IgG3 antibodies. The results presented here show that DHEA modulates the immune response against Plasmodium differently in each sex, which helps to explain the sexual dimorphism present in malaria.

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Section: Discussionsupporting

confidence: 92%

DHEA Induces Sex-Associated Differential Patterns in Cytokine and Antibody Levels in Mice Infected with Plasmodium berghei ANKA

Buendía-González

Cervantes-Candelas

Aguilar-Castro

et al. 2023

IJMS

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“…It exhibits a marked sexual dimorphism, with males showing higher parasitaemia, symptom severity and mortality than females. Sex hormones are involved in the sexual dimorphism of the immune response in malaria ( Lopes et al., 2016 ; Legorreta-Herrera et al., 2018 ; Cervantes-Candelas et al., 2021 ); oestrogens induce immunocompetence. In contrast, testosterone, the primary male hormone, generates immunosuppression ( Wichmann et al., 1996 ; Wunderlich et al., 2002 ).…”

Section: Introductionmentioning

confidence: 99%

Testosterone induces sexual dimorphism during infection with Plasmodium berghei ANKA

Aguilar-Castro

Cervantes-Candelas

Buendía-González

et al. 2022

Front. Cell. Infect. Microbiol.

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Malaria is the most lethal parasitic disease worldwide; men exhibit higher mortality and more severe symptomatology than women; however, in most studies of immune response in malaria, sex is not considered a variable. Sex hormones 17β-oestradiol and testosterone are responsible for the main physiological differences between sexes. When interacting with their receptors on different immune cells, they modify the expression of genes that modulate cell proliferation, differentiation, and synthesis of cytokines. The immunosuppressive activity of testosterone is well accepted; however, its participation in the sexual dimorphism of the immune response to malaria has not been studied. In this work, we analysed whether altering the concentration of testosterone, through increasing the concentration of this hormone for exogenous administration for three weeks, or gonadectomy before infection with Plasmodium berghei ANKA affects different cells of the immune response necessary for parasite clearance. We also assessed the concentration of pro-and anti-inflammatory cytokines in male and female CBA/Ca mice infected or not with the parasite. Our results show that testosterone changes affect females more than males, resulting in sex-associated patterns. Testosterone administration increased parasitaemia in intact males while reducing it in intact females leading to a dimorphic pattern. In addition, gonadectomy increased parasitaemia in both sexes. Moreover, testosterone administration prevented both weight loss caused by the infection in females and hypothermia in gonadectomized mice of both sexes. Boosting testosterone concentration increased CD3+ and CD8+ populations but decreased the B220+ cells exclusively in females. Additionally, testosterone reduced IFN-γ concentration and increased IL-6 levels only in females, while in males, testosterone increased the number of NK cells. Finally, gonadectomy decreased TNF-α concentration in both sexes. Our results demonstrate that testosterone induces different patterns depending on sex and testosterone concentration. The results of this work contribute to understanding the impact of modifying testosterone concentration on the immune response specific against Plasmodium and the participation of this hormone in sexual dimorphism in malaria.

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“…Previous works from different groups have shown that OVX induces neuroinflammation (overproduction of inflammatory cytokines and glial activation in CNS) and/or memory decline, depression-like behaviors in mice, [45][46][47][48][49][50][51][52][53] and in rats. [54][55][56][57][58] Consistently, in the present work we found that chronic pain and memory/emotional deficits were associated with neuroinflammation in OVX and aged female mice.…”

Section: Discussionmentioning

confidence: 99%

The Causal Role of Magnesium Deficiency in the Neuroinflammation, Pain Hypersensitivity and Memory/Emotional Deficits in Ovariectomized and Aged Female Mice

Zhang¹,

Xiong²,

Lin³

et al. 2021

JIR

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Postmenopausal women often suffer from chronic pain, memory decline and mood depression. The mechanisms underlying the neuronal disorders are not fully understood, and effective treatment is still lacking. Methods: Oral administration of magnesium-L-threonate was tested to treat the neuronal disorders in ovariectomized and aged female mice. The pain hypersensitivity, memory function and depression-like behaviors were measured with a set of behavioral tests. Western blots, immunochemistry and in situ hybridization were used to assess molecular changes. Results: Chronic oral administration of magnesium-L-threonate substantially prevented or reversed the chronic pain and memory/emotional deficits in both ovariectomized and aged female mice. We found that phospho-p65, an active form of nuclear factor-kappaB, tumor necrosis factoralpha and interleukin-1 beta were significantly upregulated in the neurons of dorsal root ganglion, spinal dorsal horn and hippocampus in ovariectomized and aged mice. The microglia and astrocytes were activated in spinal dorsal horn and hippocampus. Calcitonin gene-related peptide, a marker for peptidergic C-fibers, was upregulated in dorsal horn, which is associated with potentiation of C-fiber-mediated synaptic transmission in the model mice. In parallel with neuroinflammation and synaptic potentiation, free Mg 2+ levels in plasma, cerebrospinal fluid and in dorsal root ganglion neurons were significantly reduced. Oral magnesium-L-threonate normalized the neuroinflammation, synaptic potentiation and Mg 2+ deficiency, but did not affect the estrogen decline in ovariectomized and aged mice. Furthermore, in cultured dorsal root ganglion neurons, estrogen at physiological concentration elevated intracellular Mg 2+ , and downregulated phospho-p65, tumor necrosis factor-alpha and interleukin-1 beta exclusively in the presence of extracellular Mg 2+ . Conclusion: Estrogen decline in menopause may cause neuroinflammation by reducing intracellular Mg 2+ in neurons, leading to chronic pain, memory/emotional deficits. Supplement Mg 2+ by oral magnesium-L-threonate may be a novel approach for treating menopause-related neuronal disorders.

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Sex-Associated Differential mRNA Expression of Cytokines and Its Regulation by Sex Steroids in Different Brain Regions in aPlasmodium bergheiANKA Model of Cerebral Malaria

Cited by 4 publications

References 50 publications

DHEA Induces Sex-Associated Differential Patterns in Cytokine and Antibody Levels in Mice Infected with Plasmodium berghei ANKA

DHEA Induces Sex-Associated Differential Patterns in Cytokine and Antibody Levels in Mice Infected with Plasmodium berghei ANKA

Testosterone induces sexual dimorphism during infection with Plasmodium berghei ANKA

The Causal Role of Magnesium Deficiency in the Neuroinflammation, Pain Hypersensitivity and Memory/Emotional Deficits in Ovariectomized and Aged Female Mice

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