Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth

Abstract

Intrauterine growth restriction (IUGR) is caused by insufficient remodeling of spiral arteries (SAs). The mechanism underlying the relevance of natural killer cells (NKs) and mast cells (MCs) for SA remodeling and its effects on pregnancy outcome are not well understood. We show that NK depletion arrested SA remodeling without affecting pregnancy. MC depletion resulted in abnormally remodeled SAs and IUGR. Combined absence of NKs and MCs substantially affected SA remodeling and impaired fetal growth. We found that α-chymase mast cell protease (Mcpt) 5 mediates apoptosis of uterine smooth muscle cells, a key feature of SA remodeling. Additionally, we report a previously unknown source for Mcpt5: uterine (u) NKs. Mice with selective deletion of Mcpt5+ cells had un-remodeled SAs and growth-restricted progeny. The human α-chymase CMA1, phylogenetic homolog of Mcpt5, stimulated the ex vivo migration of human trophoblasts, a pre-requisite for SA remodeling. Our results show that chymases secreted by uMCs and uNKs are pivotal to the vascular changes required to support pregnancy. Understanding the mechanisms underlying pregnancy-induced vascular changes is essential for developing therapeutic options against pregnancy complications associated with poor vascular remodeling.

Mast cells—Good guys with a bad image?

“…Interestingly, a combined absence of MCs and NKs worsens SA remodeling when compared to single cell deficiency, suggesting that these 2 cell types have similar functionalities at least regarding SA remodeling. 115,116 We found that α-chymase Mcpt5, secreted by MCs and uNKs, is able to induce the apoptosis of uterine smooth muscle cells, a process that is very important for an efficient SA remodeling. 116 182,183,127 In guinea pig and human, it has been shown that serotonin, histamine, and prostaglandin are central players for the stimulation of the myometrial contractility as initiators of birth.…”

“…This challenging balance between immunity and specific tolerance requires a perfectly coordinated interplay of immune cells. 115 In addition, T cells, DCs, NK cells, neutrophils, macrophages, and MCs are present at the interface between mother and fetus.…”

“…However, their specific depletion or their constitutive absence in mice do not impair pregnancy outcome dramatically other than negatively affecting the remodeling of uterine spiral arteries (SA). [115][116][117] It was surprising, however, to learn that the constitutive absence of MCs in mouse models has serious consequences for the growing fetus. Moreover, depleting simultaneously NKs and MCs had drastic consequences for the progeny.…”

“…Interestingly, a combined absence of MCs and NKs worsens SA remodeling when compared to single cell deficiency, suggesting that these 2 cell types have similar functionalities at least regarding SA remodeling 115,116. Interestingly, a combined absence of MCs and NKs worsens SA remodeling when compared to single cell deficiency, suggesting that these 2 cell types have similar functionalities at least regarding SA remodeling 115,116.…”

“…Cre + R-DTA + mice, that are devoid of Mcpt5 + cells, show inefficiently remodeled SA and their fetuses are affected by IUGR at birth 115. This novel piece of information goes in hand with the fact that chymases can inhibit the growth of smooth muscle cells or even to induce apoptosis in smooth muscle cells 165,163,176,177.…”