Cotechini, Tiziana

ABSTRACTProblemPreeclampsia (PE) and fetal growth restriction (FGR) are often associated with maternal inflammation and an increased risk of cardiovascular and metabolic disease in the affected mothers. The mechanism responsible for this increased risk of subsequent disease may involve reprogramming of innate immune cells, characterized by epigenetic modifications.Method of StudyCirculating monocytes from women with PE, FGR, or uncomplicated pregnancies (control) were isolated before labor. Cytokine release from monocytes following exposure to lipopolysaccharide (LPS) and the presence of lysine 4‐trimethylated histone 3 (H3K4me3) within TNF promoter sequences were evaluated. Single‐cell transcriptomic profiles of circulating monocytes from women with PE or uncomplicated pregnancies were assessed.ResultsMonocytes from women with PE or FGR exhibited increased IL‐10 secretion and decreased IL‐1β and GM‐CSF secretion in response to LPS. While TNFα secretion was not significantly different in cultures of control monocytes versus those from complicated pregnancies with or without LPS exposure, monocytes from complicated pregnancies had significantly decreased levels of H3K4me3 associated with TNF promoter sequences. Cluster quantification and pathway analysis of differentially expressed genes revealed an increased proportion of anti‐inflammatory myeloid cells and a lower proportion of inflammatory non‐classical monocytes among the circulating monocyte population in women with PE.ConclusionsMonocytes from women with PE and FGR exhibit an immune tolerance phenotype before initiation of labor. Further investigation is required to determine whether this tolerogenic phenotype persists after the affected pregnancy and contributes to increased risk of subsequent disease.

Pregnancy complications can have long-term negative effects on the health of the affected mothers and their children. In this review, we highlight the underlying inflammatory etiologies of common pregnancy complications and discuss how aberrant inflammation may lead to the acquisition of innate immune memory. The latter can be described as a functional epigenetic reprogramming of innate immune cells following an initial exposure to an inflammatory stimulus, ultimately resulting in an altered response following re-exposure to a similar inflammatory stimulus. We propose that aberrant maternal inflammation associated with complications of pregnancy increases the cross-generational risk of developing noncommunicable diseases (i.e., pregnancy complications, cardiovascular disease, and metabolic disease) through a process mediated by innate immune memory. Elucidating a role for innate immune memory in the cross-generational health consequences of pregnancy complications may lead to the development of novel strategies aimed at reducing the long-term risk of disease.