Spontaneous miscarriages are explained by the stress/glucocorticoid/lipoxin A4 axis

Area of Science:

• Reproductive immunology
• Molecular endocrinology
• Inflammation biology

Background:

• The molecular mechanisms underlying miscarriage remain largely unknown.
• Suspected causes include endocrine, genetic, infectious, and immunological factors.
• 11β-hydroxysteroid dehydrogenase (HSD) type 2 is crucial for inactivating glucocorticoids during pregnancy.

Purpose of the Study:

• To elucidate the molecular mechanisms of early pregnancy loss.
• To investigate the role of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and lipoxin A4 (LXA4) in miscarriage.
• To identify a common molecular pathway involved in stress-induced pregnancy loss.

Main Methods:

• Analysis of 11β-HSD2, glucocorticoid activity, and LXA4 levels in women with spontaneous miscarriages and a murine model.
• Investigating the effects of LXA4 replenishment and blockade on pregnancy outcomes in mouse models.
• Examining the impact of stress and infection on the expression of 11β-HSD2 and 11β-HSD1.

Main Results:

• Downregulation of 11β-HSD2 was observed in women with miscarriage and in a murine model.
• Decreased levels of LXA4 and its biosynthetic enzymes were found in spontaneous miscarriages.
• Restoring LXA4 levels prevented LPS-induced miscarriage, while blocking LXA4 signaling induced miscarriage in mice.
• Stress or infection led to decreased 11β-HSD2 expression, increased glucocorticoid activity, and reduced LXA4.

Conclusions:

• The stress/glucocorticoid/LXA4 axis represents a potential common pathway for miscarriage.
• 11β-HSD2 downregulation and subsequent LXA4 inhibition contribute to pregnancy loss.
• LXA4 plays a protective role by modulating uterine and placental inflammation and mast cells.