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Inflammation mediated by both innate and adaptive immune cells is necessary for several important processes during pregnancy. Pro-inflammatory immune cell activation plays a critical role in embryo implantation, placentation, and parturition; however dysregulation of these cells can lead to detrimental pregnancy outcomes including spontaneous abortion, fetal growth restriction, maternal pathology including hypertensive disorders, or fetal and maternal death. The resolution of inflammation plays an important role throughout pregnancy and is largely mediated by immune cells that produce interleukin (IL)-4 and IL-10. The temporal and spatial aspects of reducing inflammation during pregnancy represent a complex process that if not functioning optimally can lead to persistent inflammation and pregnancy complications. In this review, we examine how immune cells that produce IL-4 and IL-10 are regulated throughout pregnancy as well as the effects that reduced IL-4 and IL-10 signaling has on fetal and maternal physiology. [ABSTRACT FROM AUTHOR]

The immunosuppressive drug cyclosporine A (CsA) causes systemic and renal vascular remodeling, endothelial dysfunction, and hypertension and this is associated with decreased anti-inflammatory regulatory T cells (Tregs). Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature granulocytes, macrophages, and dendritic cells, play a central regulatory role in immune responses by inhibiting various pro-inflammatory innate and adaptive immune cells as well as stimulating Treg expansion. We hypothesized that CsA causes vascular remodeling, endothelial dysfunction, and hypertension in part by decreasing MDSCs and that augmentation of MDSCs in vivo with IL-33 treatment can prevent these effects. Daily treatment of male C57BL6/J mice for 1 week with CsA (50 mg/kg/day, ip) and IL-33 (0.5 ug/day, ip) prevented the CsA-induced decrease in splenic MDSC levels (Day 7 % of lymphocytes: Con=3.7±0.9, CsA=2.1±0.5∗, CsA+IL-33=3.2±0.3; ∗p<0.05 vs. Con), increase in SBP (Day 7 SBP in mmHg: Con=94±3, CsA=148±4∗, CsA+IL-33=100±3; ∗p<0.05 vs. Con), and decrease in maximal aortic endothelium-dependent relaxation responses (Con=78±2%, CsA=29±6%∗, CsA+IL-33=74±2%; ∗p<0.05 vs. Con). Additionally, CsA treatment increased fibronectin protein levels in aortas and kidneys and caused renal intraglomerular mesangial expansion and congestion, all of which were ameliorated by co-treatment with IL-33. Together, these data suggest that the hypertension, endothelial dysfunction, and vascular remodeling caused by CsA is mediated in part by decreased MDSCs and that IL-33 treatment may have beneficial cardiovascular effects in CsA-treated patients. [ABSTRACT FROM AUTHOR]

Cyclosporine A (CsA) is an immunosuppressive drug that can cause vascular and renal endothelial dysfunction and hypertension. Myeloid-derived suppressor cells (MDSCs) exert anti-inflammatory activity by inhibiting various innate and adaptive immune cells; however, the direct effects of CsA on MDSCs and whether MDSCs can prevent the detrimental CsA effects on endothelial cells are unknown. We hypothesized that CsA directly decreases MDSCs and that MDSCs prevent CsA-induced endothelial injury. CsA (50 uM) treatment of CD11b+/Gr-1+ MDSCs isolated from male C57BL6/J mice for 24 hours caused a dose-dependent decrease in MDSCs (Total CD11b+/Gr-1+ cell number: Veh=6,358,000, CsA 10 uM=3,505,000, CsA 25 uM=2,685,000, CsA 50 uM=1,425,000). Mouse cardiac vascular and glomerular endothelial cells were treated with CsA (50 uM) in the absence and presence of 75,000 isolated MDSCs for 24 hours. CsA significantly increased fibronectin and ICAM protein levels 1.5-2-fold in both vascular and glomerular endothelial cells compared to vehicle-treated endothelial cells. The presence of MDSCs prevented the CsA-induced increase in fibronectin and ICAM while having no effects in vehicle-treated endothelial cells. Additionally, CsA (50 uM) treatment of aortas isolated from male C57BL6/J mice for 24 hours markedly decreased maximal acetylcholine-induced relaxation responses and this was partially restored by co-incubation with MDSCs, and isolated kidneys treated with CsA had increased levels of fibronectin and this was ameliorated by co-incubation with MDSCs. In conclusion, CsA-induced decreases in MDSCs may play a role in endothelial cell injury and the augmentation of MDSCs may prevent the vascular and renal dysfunction and hypertension caused by CsA. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by vascular endothelial dysfunction and excessive immunity and inflammation. Activation of the dsRNA receptor Toll-like receptor 3 (TLR3) or the ssRNA receptor TLR7 elicits a pregnancy-dependent PE-like syndrome in mice by inducing a pro-inflammatory immune response. CD74 (MHC Class II invariant chain) acts as a chaperone for MHC Class II surface expression on immune cells during antigen presentation and is cleaved into Class II-Associated Invariant Peptide (CLIP) following polyclonal activation of immune cell TLRs. The presence of CLIP in the groove of MHC Class II prevents T cell-dependent death leading to persistent immune cell activation. We hypothesized that genetic deletion of CD74 and subsequent depletion of CLIP on immune cells prevents TLR-induced immune responses and the development of PE in mice. Pregnant WT and CD74 KO mice were given i.p. injections of normal saline (P), poly I:C (TLR3 agonist; P-PIC), or R837 (TLR7 agonist; P-R837) on gestational days 13, 15, and 17 and euthanized on day 18. P-PIC and P-R837 WT mice had significantly increased splenic levels of pro-inflammatory CD3+/gd T cells and plasma levels of the gd T cell-derived cytokines IFNg, TNFa, and IL-17 compared to P WT mice whereas P-PIC and P-R837 CD74 KO mice had significantly increased anti-inflammatory CD3+/gd T cells and no significant increases in plasma IFNg, TNFa, and IL-17 levels. P-PIC and P-R837 CD74 KO mice did not develop the hypertension (gd17 SBP in mmHg: P WT=102±3, P CD74 KO=100±3, P-PIC WT=147±4∗, P-PIC CD74 KO=95±3, P-R837 WT=133±2∗, P-R837 CD74 KO=97±1; ∗p<0.05 vs. P WT), endothelial dysfunction, proteinuria, or placental necrosis seen in P-PIC and P-R837 WT mice. In conclusion, CD74 is crucial for the development of TLR-induced PE-like symptoms in mice and CD74/CLIP depletion may be a promising therapeutic target for women with PE. [ABSTRACT FROM AUTHOR]