S100 proteins: An emerging cynosure in pregnancy & adverse reproductive outcome

In maternal endometrium, S100 proteins are expressed by both immune cells and non-immune cells. A few groups of S100 proteins such as S100A8, S100A9 and S100A12 are mainly secreted from myeloid origin of immune cells such as granulocytes, monocytes and early stages of macrophages 4 . As myeloid origin cells are well known as crucial regulators for other immune cells (T, Treg, uNK and non-inflammatory macrophages and neutrophils cells) in successful pregnancy, any alteration in inflammatory or immunomodulatory stage may change S100 protein levels 4 ( Fig. 2 ). Some non-immune cells such as mice placenta and ovaries of cow and pig have been reported to secrete some S100 group proteins such as S100A1, S100A6, S100A9 and S100A8 5 48 . Schematic diagram represents interaction of S100 proteins with immune cells for the regulation of various hallmark processes of pregnancy. IFN-γ, interferon gamma; IL, interleukin; TH, T helper; TNF-α, tumor necrosis factor alpha; uNK, uterine natural killer. Source : Refs 4 47 . S100 proteins regulate embryo implantation, intrauterine growth and normal foetal brain development during pregnancy. S100 family proteins have been found to be dysregulated in various endometrial diseases ( Table II ). S100A8 proteins are found to be down regulated in receptive phase of endometrium 57 . S100A8 protein recruits mouse and human neutrophils and macrophages at the site of inflammation 58 . Endometrial epithelium and stromal cells also showed expression of S100A10 protein during the implantation window and found to play an important role in endometrial receptivity 54 . The expression of these proteins have been found to be down regulated in the endometrium of infertile patients 54 55 . This is the reason behind the failure of 30 per cent of embryo implantation in assisted reproduction. Altered expression profile of S100 proteins in various human pregnancy-related diseases IUGR, intrauterine growth restriction; SGA, small for gestational age; IVF, in vitro fertilization; PCOS, polycystic ovary syndrome A study conducted by Passey et al 5 showed that S100A8 knockout gene in mice caused a late embryonic lethality and suggested its role in fetomaternal tolerance. A study on transcriptome-based analysis in equine pregnancy revealed that S100A6 protein was expressed in conceptus side, and S100A2, S100A4, S100A6 and S100A8 were present in maternal endometrium on day 16 in mare 59 . A key role of these proteins has been suggested in epidermal growth factor-stimulated embryo adhesion, acquisition of endometrial receptivity, immunotolerance, apoptosis of dead endometrial epithelial cells and prolactin secretion, a marker for onset of decidualization 60 61 . S100 β protein is also found to be up regulated in trisomy cases, and their upregulation is an indicator of a brain lesion in developing foetus 58 . Thus, monitoring of S100 protein could be helpful in the detection of brain distress in intrauterine growth-retarded (IUGR) foetuses 50 . In preeclampsia and IUGR cases, amniotic fluid S100B protein concentration was found to be elevated 23 .

Function of S100 proteins is determined by their oligomeric forms and their respective binding partners 46 . Extracellular S100 proteins act via activation of surface receptors such as G protein-coupled receptors, receptor for advanced glycation end products (RAGEs) and toll-like receptors and aid in regulatory processes such as cell proliferation, differentiation and migration in normal as well as different pathological conditions. Intracellular S100 proteins also act via interaction with different target enzymes, cytoskeleton subunits, receptors and transcription factors or nucleic acids regulate Ca 2+ homeostasis, energy metabolism and cellular differentiation.

Early miscarriage and pregnancy-associated problems are of major concern. The reason behind this is not only genetical or physiological but also environmental and modern lifestyle. Moderate levels of inflammatory reactions are also pre-requisite during the first trimester of pregnancy for implantation and embryo development. These early stages of pregnancy resemble ‘an open wound’ 1 . For invasion and proper blood supply of embryo neovascularization and tissue remodelling occur during early gestational weeks of pregnancy 1 2 . An appropriate tuning of anti-inflammatory and inflammatory mediators is required for adequate repair of the uterine epithelium and the removal of cellular debris. Thus, this critical period of pregnancy is marked by expression of specific cytokines and adhesion molecules by both foetal and maternal side ensuring successful pregnancy. Any alteration and dysfunction of this balanced inflammatory milieu and any perturbation or disturbance in this during the critical period result in miscarriage or pregnancy-associated complications 3 . Earlier studies in mice and human revealed the role of important calcium (Ca 2+ )-binding S100 proteins in pregnancy-related complications 4 5 . This group of proteins helps in the recruitment of leucocytes at inflammatory site and functions like cytokines 4 . These proteins regulate a variety of cellular functions such as cellular differentiation, cell cycle progression and energy intracellular signal transduction by interacting with several other mediatory proteins 6 . S100 proteins were found to be tumorigenic in function and get elevated in several cancer and melanoma cases 6 . An earlier study in human also showed elevated level of S100 group proteins in high-risk pregnancy cases, in amniotic fluid and cord blood of foetus with brain damage 7 . The role of S100 protein in immunomodulation of high-risk pregnancy cases is an active area of research and clinical investigation. This review focuses on new advances regarding the role of S100 protein in diagnosis and treatment of high-risk pregnancies.

The present review summarizes the role of S100 proteins in high-risk pregnancy cases along with its structure and mechanism of action. This also covers the importance of S100 proteins as a main player of successful implantation, embryonic growth and birth of physically and mentally healthy child. The optimal expression and signalling of S100 proteins, at particular stages of pregnancy is a pre-requisite for avoiding high-risk pregnancy cases and can serve as therapeutic target and prognostic biomarker in pregnancy-related complications. The first author (RV) and the second author (PV) acknowledge the Department of Biotechnology, New Delhi, India, for providing financial assistance in the form of Research Associateship and Senior Research Fellowship, respectively. The third author (SB) thanks the University Grant Commission, New Delhi, India, for providing financial assistance in the form of Senior Research Fellowship. None.