Maternal Obesity and the Uterine Immune Cell Landscape: The Shaping Role of Inflammation

Abstract

Inflammation is often equated to the physiological response to injury or infection. Inflammatory responses defined by cytokine storms control cellular mechanisms that can either resolve quickly (i.e., acute inflammation) or remain prolonged and unabated (i.e., chronic inflammation). Perhaps less well-appreciated is the importance of inflammatory processes central to healthy pregnancy, including implantation, early stages of placentation, and parturition. Pregnancy juxtaposed with disease can lead to the perpetuation of aberrant inflammation that likely contributes to or potentiates maternal morbidity and poor fetal outcome. Maternal obesity, a prevalent condition within women of reproductive age, associates with increased risk of developing multiple pregnancy disorders. Importantly, chronic low-grade inflammation is thought to underlie the development of obesity-related obstetric and perinatal complications. While diverse subsets of uterine immune cells play central roles in initiating and maintaining healthy pregnancy, uterine leukocyte dysfunction as a result of maternal obesity may underpin the development of pregnancy disorders. In this review we discuss the current knowledge related to the impact of maternal obesity and obesity-associated inflammation on uterine immune cell function, utero-placental establishment, and pregnancy health.

Maternal Low-Grade Chronic Inflammation and Intrauterine Programming of Health and Disease

“…Obesity-driven inflammation has further shown associations with trophoblast development and function in animal models, where leptin and low-density lipoproteins are able to regulate trophoblast apoptosis, proliferation, and migration in culture [ 2 ]. Consistently, high-fat-fed animals showed impaired uterine vascular remodeling, placental angiogenic defects, poor decidualization, and smaller implantation site in obese early pregnancy [ 41 , 42 ].…”

“…Human studies confirmed the role of several adipokines (i.e., leptin) in regulating placental angiogenesis, protein synthesis, and growth, finally impacting placental function in obese mothers [ 43 , 44 ]. Transcriptomic analyses of human obese placentas confirmed an increased expression of genes related to lipid metabolism, angiogenesis, and hormone/cytokine activity, resulting in a lipotoxic placental environment characterized by decreased vasculogenesis, increased oxidative stress, and fetoplacental hypoxia [ 2 , 45 ]. Moreover, placental metabolome analysis of obese pregnancies has also recently shown different patterns of amino acid profiles and mitochondrial function, supporting a shift towards higher placental metabolism.…”

“…Despite the myth of transplant allografts raising the idea that systemic immune suppression is an essential feature of pregnancy, the last decades of research revealed a more complex fetal–maternal immune interaction, involving both local and systemic inflammation as a crucial component of healthy pregnancies [ 1 , 2 ]. Starting with local inflammation, the human maternal–fetal interface involves a high number of immune cells, including macrophages, regulatory T cells, natural killers, and dendritic cells, which coordinate critical events of implantation, placental development, and finally delivery [ 1 , 3 , 4 ].…”

Obesity Challenge Drives Distinct Maternal Immune Response Changes in Normal Pregnant and Abortion-Prone Mouse Models

“…The long-term presence of these pro-inflammatory factors not only induces systemic inflammation but also gives a rise to immune cell alterations at distal organ sites, leading to multi-organ dysfunction ( 17 ). Therefore, it is unsurprising that obesity-related stress alters the immune environment at the maternal–fetal interface, disrupting normal placental function which can lead to pregnancy failure ( 18 ). Several reported studies appear to verify this hypothesis.…”

Maternal Obesity Does Not Exacerbate the Effects of LPS Injection on Pregnancy Outcomes in Mice

“…It has been suggested that inflammation, rather than obesity per se, affects the risk of adverse outcome [ 5 , 6 ]. Specifically, it is hypothesized that increased adipose tissue results in elevated levels of pro-inflammatory cytokines in the blood [ 7 , 8 , 9 ], which influence the function of immune cells within the uterus [ 5 ], thereby impairing normal placental development and increasing the risk of adverse outcomes [ 10 , 11 ]. While maternal obesity alone does not necessarily lead to complications, the associated chronic, low-grade inflammation might increase susceptibility to adverse outcomes when combined with an additional inflammatory challenge.…”