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Immune modulatory effects of progesterone on oxLDL-induced trained immunity in monocytes
Laszlo A Groh1, Dagmar E Verel1, Charlotte D C C van der Heijden1
1Department of Internal Medicine, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
Insights
Progesterone uniquely suppresses trained immunity in monocytes exposed to oxidized low-density lipoproteins (oxLDL), potentially explaining lower cardiovascular disease (CVD) risk in premenopausal women.
Area of Science:
- Immunology
- Endocrinology
- Cardiovascular Science
Background:
- Atherosclerotic cardiovascular diseases (CVD) are a major global health concern.
- Monocyte-derived macrophages play a critical role in atherosclerosis development.
- Trained immunity, an innate immune memory, can be induced by oxidized low-density lipoproteins (oxLDL) and contributes to atherogenesis.
Purpose of the Study:
- To investigate the intracellular mechanisms underlying oxLDL-induced trained immunity.
- To explore the role of intracellular steroid hormones in oxLDL-induced trained immunity.
- To determine the effect of specific steroid hormones on oxLDL-induced trained immunity.
Main Methods:
- Untargeted intracellular metabolomics in human primary monocytes.
- Monocyte co-stimulation with oxLDL and various steroid hormones (progesterone, hydrocortisone, dexamethasone, β-estradiol, dihydrotestosterone).
- Analysis of cytokine production (TNFα, IL-6) and correlation of single nucleotide polymorphisms (SNPs) in nuclear receptors with trained immunity.
Main Results:
- oxLDL-induced trained immunity alters intracellular steroid hormone balance in monocytes.
- Progesterone uniquely attenuated enhanced TNFα and IL-6 production in trained monocytes.
- SNPs in nuclear glucocorticoid, progesterone, and mineralocorticoid receptors correlated with oxLDL-induced trained immunity.
- Progesterone suppressed TNFα via glucocorticoid and mineralocorticoid receptors.
Conclusions:
- Progesterone demonstrates a unique capacity to suppress oxLDL-induced trained immunity.
- This progesterone-mediated suppression may involve nuclear glucocorticoid and mineralocorticoid receptors.
- The findings suggest a potential mechanism for the lower CVD incidence observed in premenopausal women.
Abstract:
Atherosclerotic cardiovascular diseases (CVD) are among the leading causes of death in the world. Monocyte-derived macrophages are key players in the pathophysiology of atherosclerosis. Innate immune memory following exposure of monocytes to atherogenic compounds, such as oxidized low-density lipoproteins (oxLDL), termed trained immunity, can contribute to atherogenesis. The current study aimed to elucidate intracellular mechanisms of oxLDL-induced trained immunity. Using untargeted intracellular metabolomics in isolated human primary monocytes, we show that oxLDL-induced trained immunity results in alterations in the balance of intracellular steroid hormones in monocytes. This was reflected by a decrease in extracellular progesterone concentrations following LPS stimulation. To understand the potential effects of steroid hormones on trained immunity, monocytes were costimulated with oxLDL and the steroid hormones progesterone, hydrocortisone, dexamethasone, β-estradiol, and dihydrotestosterone. Progesterone showed a unique ability to attenuate the enhanced TNFα and IL-6 production following oxLDL-induced trained immunity. Single nucleotide polymorphisms in the nuclear glucocorticoid, progesterone, and mineralocorticoid receptor were shown to correlate with ex vivo oxLDL-induced trained immunity in 243 healthy volunteers. Pharmacologic inhibition experiments revealed that progesterone exerts the suppression of TNFα in trained immunity via the nuclear glucocorticoid and mineralocorticoid receptors. Our data show that progesterone has a unique ability to suppress oxLDL-induced trained immunity. We hypothesize that this effect might contribute to the lower incidence of CVD in premenopausal women.
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