Changes in immune cell distribution and their cytokine/chemokine production during regression of the rhesus macaque corpus luteum†

Bishop, Cecily V.; Xu, Fan; Steinbach, Rosemary J.; Ficco, Ellie; Hyzer, Jeffrey; Blue, Steven W.; Stouffer, Richard L.; Hennebold, Jon D.

doi:10.1093/biolre/iox052

Cited by 15 publications

(14 citation statements)

References 56 publications

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“…Of note in our non-pregnant controls, we did not control for different phases in their menstrual cycle. In non-human primates, in peripheral blood, the luteal phase of the menstrual cycle, when P4 is at peak concentration, is associated with tolerant immune responses that favor successful pregnancy ( 43 ). It is assumed these changes transfer to humans.…”

Section: Discussionmentioning

confidence: 99%

Progesterone Modulation of Pregnancy-Related Immune Responses

2018

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Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with the onset of parturition. However, the effects of P4 on adaptive immune responses are poorly understood. In this study, we took a novel approach by comparing the effects of P4 supplementation longitudinally, with treatment using a P4 antagonist mifepristone (RU486) in mid-trimester pregnancies. Thus, we were able to demonstrate the immune-modulatory functions of P4. We show that, in pregnancy, the immune system is increasingly activated (CD38, CCR6) with greater antigen-specific cytotoxic T cell responses (granzyme B). Simultaneously, pregnancy promotes a tolerant immune environment (IL-10 and regulatory-T cells) that gradually reverses prior to the onset of labor. P4 suppresses and RU486 enhances antigen-specific CD4 and CD8 T cell inflammatory cytokine (IFN-γ) and cytotoxic molecule release (granzyme B). P4 and RU486 effectively modulate immune cell-mediated interactions, by regulating differentiated memory T cell subset sensitivity to antigen stimulation. Our results indicate that P4 and RU486, as immune modulators, share a reciprocal relationship. These data unveil key contributions of P4 to the modulation of the maternal immune system and suggests targets for future modulation of maternal immune function during pregnancy.

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Section: Discussionmentioning

confidence: 99%

Progesterone Modulation of Pregnancy-Related Immune Responses

2018

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“…Both are immunologically silent events, yet other forms of cell death attract immune cells. Immune cells, for example, macrophages, appear to play an indispensable role in ovarian functions 9 and CD11b positive macrophages invade the nonhuman primate CL during its regression and produce various cytokines and chemokines 10 .…”

Section: Introductionmentioning

confidence: 99%

Necroptosis in primate luteolysis: a role for ceramide

Bagnjuk¹,

Stöckl²,

Fröhlich³

et al. 2019

Cell Death Discovery

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The corpus luteum (CL) is a transient endocrine organ, yet molecular mechanisms resulting in its demise are not well known. The presence of phosphorylated mixed lineage kinase domain-like pseudokinase pMLKL(T357/S358) in human and nonhuman primate CL samples (Macaca mulatta and Callithrix jacchus) implied that necroptosis of luteal cells may be involved. In M. mulatta CL, pMLKL positive staining became detectable only from the mid-late luteal phase onwards, pointing to necroptosis during regression of the CL. Cell death, including necroptosis, was previously observed in cultures of human luteal granulosa cells (GCs), an apt model for the study of the human CL. To explore mechanisms of necroptotic cell death in GCs during culture, we performed a proteomic analysis. The levels of 50 proteins were significantly altered after 5 days of culture. Interconnectivity analysis and immunocytochemistry implicated specifically the ceramide salvage pathway to be enhanced. M. mulatta CL transcriptome analysis indicated in vivo relevance. Perturbing endogenous ceramide generation by fumonisin B1 (FB1) and addition of soluble ceramide (C2-CER) yielded opposite actions on viability of GCs and therefore supported the significance of the ceramide pathway. Morphological changes indicated necrotic cell death in the C2-CER treated group. Studies with the pan caspase blocker zVAD-fmk or the necroptosis blocker necrosulfonamid (NSA) further supported that C2-CER induced necroptosis. Our data pinpoint necroptosis in a physiological process, namely CL regression. This raises the possibility that the primate CL could be rescued by pharmacological inhibition of necroptosis or by interaction with ceramide metabolism.

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“…CD11b is expressed on the surface of many leukocytes, including neutrophils, monocytes, natural killer cells, macrophages and granulocytes, and F4/80 is a marker of macrophages [21]. Thus, we examined infiltration of inflammatory cells in colon tissues by using CD11b + and F4/80 as a marker to monitor inflammation process.…”

Section: Resultsmentioning

confidence: 99%

MMI-0100 Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice through Targeting MK2 Pathway

et al. 2019

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Backgrounds: This study aimed to investigate the protective effects of MMI-0100, a cell-penetrating peptide inhibitor of MAPK-activated protein kinase II (MK2), on acute colitis induced by dextran sodium sulfate (DSS). Mice were injected intraperitoneally with different doses of MMI-0100 (0.5 and 1 mg/kg per day, six days). The physiological indexes, the parameters for colonic pathological injury and the intensity of inflammatory responses were evaluated by histological staining, quantitative PCR, western blotting, and immunostaining. MMI-0100 attenuated DSS-induced body weight loss, colon length shortening, and colonic pathological injury, including decreased myeloperoxidase (MPO) and inhibited inflammatory cell infiltration. MMI-0100 suppressed DSS-induced activation of CD11b+ and F4/80 positive cell, and dramatically decreased the expression of a series of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, TGF- β, IFN-γ, IL-17A, COX-2 and iNOS. A TUNEL assay showed that MMI-0100 protected against DSS-induced apoptosis. This is consistent with the results of Western blotting assay in apoptosis-related proteins including Bcl-2, BAX, caspase-3. The anti-inflammatory effects of MMI-0100 on DSS-induced colitis were achieved by down-regulating the phosphorylation level of MK2, IκBα and p65 protein. The current study clearly demonstrates a protective role for MMI-0100 in experimental IBD.

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Changes in immune cell distribution and their cytokine/chemokine production during regression of the rhesus macaque corpus luteum†

Cited by 15 publications

References 56 publications

Progesterone Modulation of Pregnancy-Related Immune Responses

Progesterone Modulation of Pregnancy-Related Immune Responses

Necroptosis in primate luteolysis: a role for ceramide

MMI-0100 Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice through Targeting MK2 Pathway

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