Heme Oxygenase Protects against Placental Vascular Inflammation and Abortion by the Alarmin Heme in Mice

Abstract

Both infectious as non-infectious inflammation can cause placental dysfunction and pregnancy complications. During the first trimester of human gestation, when palatogenesis takes place, intrauterine hematoma and hemorrhage are common phenomena, causing the release of large amounts of heme, a well-known alarmin. We postulated that exposure of pregnant mice to heme during palatogenesis would initiate oxidative and inflammatory stress, leading to pathological pregnancy, increasing the incidence of palatal clefting and abortion. Both heme oxygenase isoforms (HO-1 and HO-2) break down heme, thereby generating anti-oxidative and -inflammatory products. HO may thus counteract these heme-induced injurious stresses. To test this hypothesis, we administered heme to pregnant CD1 outbred mice at Day E12 by intraperitoneal injection in increasing doses: 30, 75 or 150 μmol/kg body weight (30H, 75H or 150H) in the presence or absence of HO-activity inhibitor SnMP from Day E11. Exposure to heme resulted in a dose-dependent increase in abortion. At 75H half of the fetuses where resorbed, while at 150H all fetuses were aborted. HO-activity protected against heme-induced abortion since inhibition of HO-activity aggravated heme-induced detrimental effects. The fetuses surviving heme administration demonstrated normal palatal fusion. Immunostainings at Day E16 demonstrated higher numbers of ICAM-1 positive blood vessels, macrophages and HO-1 positive cells in placenta after administration of 75H or SnMP + 30H. Summarizing, heme acts as an endogenous “alarmin” during pregnancy in a dose-dependent fashion, while HO-activity protects against heme-induced placental vascular inflammation and abortion.

The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss*

“…135,136 A recent work confirmed HO activity protected against hemeinduced abortion. 137 In particular, inflammatory response induced by heme or inhibition of HO activity led to endothelial cell activation and upregulation of intercellular adhesion molecule 1 (ICAM-1), facilitating the recruitment of placenta macrophages to ultimately increasing the risk of pregnancy loss. 137 Heme has been reported either to polarize macrophages to a pro-inflammatory status (also known as M1) or to induce an anti-inflammatory status (M2).…”

“…137 In particular, inflammatory response induced by heme or inhibition of HO activity led to endothelial cell activation and upregulation of intercellular adhesion molecule 1 (ICAM-1), facilitating the recruitment of placenta macrophages to ultimately increasing the risk of pregnancy loss. 137 Heme has been reported either to polarize macrophages to a pro-inflammatory status (also known as M1) or to induce an anti-inflammatory status (M2). 138 For instance, CD163-mediated Hb-heme intake induced the expression of HO-1 and ferritin in macrophages and encouraged a M2 phenotype accompanied by the production of IL-10.…”

“…139,140 However, Linzke et al proposed that the absence of HO-1 promoted the M1 polarization of uterine Mφ, 141 thereby reducing uNK cell number by downregulating IL-15. 137,141 These controversial findings suggested the effect of heme on macrophages should be multifaceted.…”

“…For instance, CD163‐mediated Hb‐heme intake induced the expression of HO‐1 and ferritin in macrophages and encouraged a M2 phenotype accompanied by the production of IL‐10 139,140 . However, Linzke et al proposed that the absence of HO‐1 promoted the M1 polarization of uterine Mφ, 141 thereby reducing uNK cell number by downregulating IL‐15 137,141 . These controversial findings suggested the effect of heme on macrophages should be multifaceted.…”