Neuroimmune-Endocrine Interactions during Early Pregnancy in an Autoimmune Context: Focus on Macrophage Activation

Abstract

Neuroimmune-endocrine interactions seem to be central to the dialogue between the mother and the growing embryo during normal pregnancy. A proinflammatory Th1 microenvironment appears to be associated with embryo implantation but an excess of these cytokines may be deleterious. When normal gestation is subjected to stressful stimuli as those provided by a chronic inflammatory milieu, the activation profile of T cells and macrophages may be temporarily changed. Although much evidence supports the protective role of pregnancy in Th1 autoimmune diseases, the comprehension of the maternofetal interaction in an inflammatory context may serve to get more insight into pregnancy failures. Macrophages integrate multiple inputs and signals of neuroimmune-endocrine systems and they appear as major participants in either embryo implantation or loss. Changes at the macrophage level during gestation might help to understand their regulatory role in embryo implantation as well as to disclose their local and systemic pathogenic potential.

Perinatal depression—The fourth inflammatory morbidity of pregnancy?

“…Researchers initially believed that pregnancy must be a state of immune suppression – a state generated to avoid maternal attack on the foreign body growing within her, but a state that left her vulnerable to pathogenic attack herself (Kraus et al 2010, Chen et al 2012, Kraus et al 2012, Pazos et al 2012). Early pregnancy offered evidence of a proinflammatory Th1 environment, essential to implantation, whereas later pregnancy seemed to be characterized by a decrease in Th1 activity and an increase in Th2 cells, which are both tolerant of paternal antigens and supported by progesterone (Larocca et al 2008). The improvement of Th1 autoimmune diseases such as rheumatoid arthritis during pregnancy and the worsening of those characterized by Th2 dominance (such as lupus) was seen as evidence of this theory (Larocca et al 2008, Groer et al 2011).…”

“…Early pregnancy offered evidence of a proinflammatory Th1 environment, essential to implantation, whereas later pregnancy seemed to be characterized by a decrease in Th1 activity and an increase in Th2 cells, which are both tolerant of paternal antigens and supported by progesterone (Larocca et al 2008). The improvement of Th1 autoimmune diseases such as rheumatoid arthritis during pregnancy and the worsening of those characterized by Th2 dominance (such as lupus) was seen as evidence of this theory (Larocca et al 2008, Groer et al 2011). More recently, a more complex model has emerged, with macrophages as the central mediators of complex endocrine, neural, and immune mechanisms.…”

“…Macrophages produce the major proinflammatory cytokines and contain receptors for both estrogen and serotonin. Their presence is essential at various key points of gestation (implantation, parturition), but an excess of macrophages at other points in pregnancy is a sign of excess inflammation that may lead to pregnancy morbidity (Larocca et al 2008, Kraus et al 2012). …”

Factors Associated With Second-Trimester Pregnancy Loss in Women With Normal Uterine Anatomy Undergoing In Vitro Fertilization

“…[17][18][19] Obesity alters gene expression in pregnancy 20 and may increase loss through obesitydriven chronic inflammation. 21 Locally, obesogenic chronic inflammation might disrupt signaling pathways in the decidua basalis or placenta 22 ; systemically, it may alter hypothalamic-pituitary signaling and blunt ovarian response. 23 Excess estrogen in obesity may alter uterine size, receptivity, or ovarian signaling to increase loss.…”

Contribution of Vasoactive Intestinal Peptide to Immune Homeostasis in Trophoblast-Maternal Leukocyte Interaction under LPS Stimulation

“…Moreover, treatment of first-trimester trophoblast cells with the TLR-2 ligand peptidoglycan (PDG) could directly induce trophoblast cell apoptosis, while ligation of TLR-4 by the lipopolysaccharide (LPS) representing a Gram-negative bacterial infection promotes a classical inflammatory response characterized by the induction of cytokine production [11]. Thus, a successful pregnancy depends on a tight homeostatic and temporal control which is provided by redundant circuits of cell-to-cell interaction as well as local mediators targeting multiple cells to sustain the suppressor/tolerant microenvironment [12,13,14]. …”