Intra-Amniotic IL-1β Induces Fetal Inflammation in Rhesus Monkeys and Alters the Regulatory T Cell/IL-17 Balance

Abstract

Very low birth weight preterm newborns are susceptible to the development of debilitating inflammatory diseases, many of which are associated with chorioamnionitis. To define the effects of chorioamnionitis on the fetal immune system, IL-1β was administered intra-amniotically at ∼80% gestation in rhesus monkeys. IL-1β caused histological chorioamnionitis as well as lung inflammation (infiltration of neutrophils or monocytes in the fetal airways). There were large increases of multiple pro-inflammatory cytokine mRNAs in the lungs 24 h post-administration, which remained elevated relative to controls at 72 h. Intra-amniotic IL-1β also induced sustained expression of the surfactant proteins in the lungs. Importantly, IL-1β significantly altered the balance between inflammatory and regulatory T cells (Treg cells). Twenty-four h after IL-1β injection, the frequency of CD3+CD4+FOXP3+ T cells was decreased in lymphoid organs. In contrast, IL-17A–producing cells (CD3+CD4+, CD3+CD4−, and CD3−CD4− subsets) were increased in lymphoid organs. The frequency of IFN-γ-expressing cells did not change. In this model of a single exposure to an inflammatory trigger, CD3+CD4+FOXP3+ cells rebounded quickly and their frequency was increased at 72 h compared to controls. IL-17 expression was also transient. Interestingly, the T cell profile alteration was confined to the lymphoid organs and not to circulating fetal T cells. Together, these results suggest the chorioamnionitis-induced IL-1/IL-17 axis is involved in the severe inflammation that can develop in preterm newborns. Boosting Treg cells and/or controlling IL-17 may provide a means to ameliorate these abnormalities.

Chorioamnionitis-induced fetal gut injury is mediated by direct gut exposure of inflammatory mediators or by lung inflammation

“…In this regard, we previously demonstrated that the posterior mediastinal lymph node responds with a doubling of weight and increased trafficking of activated neutrophils and monocytes as a result of intrauterine lung inflammation (20). We recently demonstrated that IA LPS injection decreased Tregs and increased IL-17-producing cells in the posterior mediastinal lymph node of fetal rhesus macaques (22). Interestingly, these profound changes in the local lymph nodes were not paralleled by changes in the blood cells, showing compartmentalization of the FIRS responses after chorioamnionitis.…”

An imbalance between innate and adaptive immune cells at the maternal–fetal interface occurs prior to endotoxin-induced preterm birth

“…Current hypotheses suggest that an imbalance between CD41 Tregs and Th17 cells, T cells with opposing actions, underlies the pathophysiology of immune diseases, 68 inflammatory processes, 69 and pregnancy pathologies such as PTB. 70 Indeed, there is an increase of Th17 cells in the chorioamniotic membranes from women who underwent preterm labor with acute chorioamnionitis. 44 Our results did not support this hypothesis at the maternal-fetal interface since no changes were observed in uterine Th1, Th17, or Th9 cells prior to LPS-induced PTB.…”

Distinct functional programming of human fetal and adult monocytes

“…Sample size for statistical calculations was determined by use of the maximum number of unique biological replicates available. All experiments were performed two or more times with distinct biological samples (total of [8][9][10][11][12]. Each individual experiment contained a minimum of 4 ABM and 4 FBM samples.…”

“…4 In contrast, production of inflammatory cytokines (eg, interferon-g [IFN-g], interleukin-6 [IL-6], tumor necrosis factor a, and IL-1) in response to bacterial infection characterizes the fetal inflammatory response syndrome (FIRS), which is associated with spontaneous abortion or preterm labor. [5][6][7][8][9][10] The fetal immune system actively contributes to tolerance of maternal antigens. 1,11 Upon stimulation with noninherited maternal alloantigens, fetal naïve CD4 1 T cells preferentially differentiate into…”