Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

Solano, María Emilia; Kowal, Mirka Katharina; O’Rourke, Greta; Horst, Andrea Kristina; Modest, Kathrin; Plösch, Torsten; Barikbin, R; Remus, Chressen Catharina; Berger, Robert; Jago, C.A.; Ho, Hoang; Sass, Gabriele; Parker, Victoria J.; Lydon, John P.; DeMayo, Francesco J.; Hecher, Kurt; Karimi, Khalil; Arck, Petra C.

doi:10.1172/jci68140

Cited by 70 publications

(67 citation statements)

References 89 publications

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“…It is thought that reduced DC maturation avoided the priming of effector T cells in the mother, which protected embryo from the immune response. These mechanisms were supported by recent data suggesting that progesterone regulates both the expansion of regulatory CD8 + CD122 + T cells and the establishment of fetal tolerance after inducing expression of HO‐1 in the placenta . In addition, the progesterone–HO‐1 system reduced the expansion of cytotoxic CD8 + T cells that recognize non‐self antigens expressed by the embryo .…”

Section: The Ho‐1–co System Reduces Pathologies Caused By the Immune supporting

confidence: 54%

“…These mechanisms were supported by recent data suggesting that progesterone regulates both the expansion of regulatory CD8 + CD122 + T cells and the establishment of fetal tolerance after inducing expression of HO-1 in the placenta. 132 In addition, the progesterone-HO-1 system reduced the expansion of cytotoxic CD8 + T cells that recognize non-self antigens expressed by the embryo. 132 Consistently, a correlation was shown for pregnant women between current miscarriage and a reduced amount of regulatory T cells, despite having regular numbers of circulating DCs.…”

Section: Ho-1 Reduces Innate Immunity-mediated Inflammatory Diseasesmentioning

confidence: 99%

“…132 In addition, the progesterone-HO-1 system reduced the expansion of cytotoxic CD8 + T cells that recognize non-self antigens expressed by the embryo. 132 Consistently, a correlation was shown for pregnant women between current miscarriage and a reduced amount of regulatory T cells, despite having regular numbers of circulating DCs. 133 These data suggest that HO-1 regulates DC activity and the capacity to induce T-cell-mediated tolerance.…”

Section: Ho-1 Reduces Innate Immunity-mediated Inflammatory Diseasesmentioning

confidence: 99%

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Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

et al. 2016

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SummaryHaem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC-and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases.

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Section: The Ho‐1–co System Reduces Pathologies Caused By the Immune supporting

confidence: 54%

Section: Ho-1 Reduces Innate Immunity-mediated Inflammatory Diseasesmentioning

confidence: 99%

Section: Ho-1 Reduces Innate Immunity-mediated Inflammatory Diseasesmentioning

confidence: 99%

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Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

et al. 2016

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“…This finding is consistent with previous reports demonstrating that progesterone regulates CD8+ T cell cytokine release and cytotoxicity during pregnancy. 183,184 CD8+CD25+ T cells expressing Foxp3 seem to share phenotypic, functional, and mechanistic actions with the classical CD4+ Tregs; therefore, they were named CD8+ Tregs. 185 CD8+Foxp3+ T cells increased in vivo in response to inflammation induced by IL-6.…”

Section: Commentmentioning

confidence: 99%

Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface

Furcron

Romero

Plazyo

et al. 2015

American Journal of Obstetrics and Gynecology

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OBJECTIVE Progestogen (vaginal progesterone or 17-alpha-hydroxyprogesterone caproate [17OHP-C]) administration to patients at risk for preterm delivery is widely used for the prevention of preterm birth (PTB). The mechanisms by which these agents prevent PTB are poorly understood. Progestogens have immunomodulatory functions; therefore, we investigated the local effects of vaginal progesterone and 17OHP-C on adaptive and innate immune cells implicated in the process of parturition. STUDY DESIGN Pregnant C57BL/6J mice received vaginal progesterone (1 mg per 200 μL, n = 10) or Replens (control, 200 μL, n = 10) from 13 to 17 days postcoitum (dpc) or were subcutaneously injected with 17OHP-C (2 mg per 100 μL, n = 10) or castor oil (control, 100 μL, n = 10) on 13, 15, and 17 dpc. Decidual and myometrial leukocytes were isolated prior to term delivery (18.5 dpc) for immunophenotyping by flow cytometry. Cervical tissues were collected to determine matrix metalloproteinase (MMP)-9 activity by in situ zymography and visualization of collagen content by Masson’s trichrome staining. Plasma concentrations of progesterone, estradiol, and cytokines (interferon [IFN]-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC/GRO, and tumor necrosis factor-α) were quantified by enzyme-linked immunosorbent assays. Pregnant mice pretreated with vaginal progesterone or Replens were injected with 10 μg of an endotoxin on 16.5 dpc (n = 10 each) and monitored via infrared camera until delivery to determine the effect of vaginal progesterone on the rate of PTB. RESULTS The following results were found: (1) vaginal progesterone, but not 17OHP-C, increased the proportion of decidual CD4+ T-regulatory cells; (2) vaginal progesterone, but not 17OHP-C, decreased the proportion of decidual CD8+CD25+Foxp3+ T cells and macrophages; (3) vaginal progesterone did not cause an M1→M2 macrophage polarization but reduced the proportion of myometrial IFNγ+ neutrophils and cervical active MMP-9-positive neutrophils and monocytes; (4) 17OHP-C did not reduce the proportion of myometrial IFNy-positive neutrophils; however, it increased the abundance of cervical active MMP-9-positive neutrophils and monocytes; (5) vaginal progesterone immune effects were associated with reduced systemic concentrations of IL-1β but not with alterations in progesterone or estradiol concentrations; and (6) vaginal progesterone pretreatment protected against endotoxin-induced PTB (effect size 50%, P = .008). CONCLUSION Vaginal progesterone, but not 17OHP-C, has local antiinflammatory effects at the maternal-fetal interface and the cervix and protects against endotoxin-induced PTB.

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“…Flow cytometric analyses of a distinct, pregnancyprotective CD8 subpopulation co-expressing CD122 in uterus-draining lymph nodes 22 Figure S2E). The frequency of DCs, defined as CD11c þ , also remained unaffected on injection of both APAP dosages after 24 hours ( Figure 2B) and 96 hours (data not shown).…”

Section: Apap Affects Maternal Immune Adaptation To Pregnancymentioning

confidence: 99%

Prenatal Acetaminophen Affects Maternal Immune and Endocrine Adaptation to Pregnancy, Induces Placental Damage, and Impairs Fetal Development in Mice

Thiele

Solano

Huber

et al. 2015

The American Journal of Pathology

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Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans.

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Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

Cited by 70 publications

References 89 publications

Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface

Prenatal Acetaminophen Affects Maternal Immune and Endocrine Adaptation to Pregnancy, Induces Placental Damage, and Impairs Fetal Development in Mice

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