Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming

Norlander, Allison E.; Bloodworth, Melissa H.; Toki, Shinji; Zhang, Jian; Zhou, Weisong; Boyd, Kelli L.; Polosukhin, Vasiliy V.; Cephus, Jacqueline-Yvonne; Ceneviva, Zachary J; Gandhi, Vivek; Chowdhury, Nowrin U; Charbonnier, Louis-Marie; Rogers, Lisa M.; Wang, Janey; Aronoff, David M.; Bastarache, Lisa; Newcomb, Dawn C.; Chatila, Talal; Peebles, R. Stokes

doi:10.1172/jci140690

Cited by 13 publications

(15 citation statements)

References 71 publications

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“…AR signaling was also recently shown in Sertoli cells to decrease Gata2 protein expression (65). However, in the prostate cancer cell lines, Gata2 is one of the transcription factors that regulates Ar expression (66,67). Therefore, in our study we determined that 5α-DHT decreased Gata2 and Il1rl1 (ST2) expression in IL-33 stimulated Tregs and that there was no difference in Ar expression in vehicle and 5α-DHT treated cells.…”

Section: St2 Expression On T Cells Including Tregs and Other Immune C...mentioning

confidence: 77%

Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation

Gandhi¹,

Cephus²,

Norlander³

et al. 2022

Journal of Clinical Investigation

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Women have higher prevalence of asthma compared to men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. Foxp3+ Tregs suppress and ST2+ Tregs promote allergic airway inflammation. Clinical studies showed the androgen, dehydroepiandrosterone (DHEA), reduced asthma symptoms in patients, and mouse studies showed androgen receptor (AR) signaling decreased allergic airway inflammation. Yet, the role of AR signaling on lung Tregs remains unclear. Using AR deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext, allergen) challenge by stabilizing Foxp3+ Tregs and limiting the number of ST2+ ex-Tregs and IL-13+ Th2 and ex-Tregs. AR signaling also decreased Alt Ext-induced ST2+ Tregs in mice by limiting Gata2 expression, a transcription factor for ST2, and by decreasing Alt Ext-induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5αdihydrotestosterone (DHT), an androgen, decreased IL-33-induced ST2 expression in lung Tregs and decreased Alt Ext induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.

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Section: St2 Expression On T Cells Including Tregs and Other Immune C...mentioning

confidence: 77%

Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation

Gandhi¹,

Cephus²,

Norlander³

et al. 2022

Journal of Clinical Investigation

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“…However, it is very likely that, in our system, the pro‐inflammatory effects of PGD 2 are masked by PGE 2 as has been shown elsewhere (Pettipher et al , 2007). Recently, another anti‐inflammatory prostanoid, PGI 2 , has been shown to drive Tregs in both human and mice via the repression of β‐catenin signaling, thus preventing Treg reprogramming toward a pathogenic phenotype (Norlander et al , 2021). Mice deficient for the PGI 2 receptor IP had significantly enhanced OVA‐elicited AAI in comparison to mice with intact PGI 2 signaling.…”

Section: Discussionmentioning

confidence: 99%

Helminthic dehydrogenase drives PGE ₂ and IL‐10 production in monocytes to potentiate Treg induction

et al. 2022

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Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation. Here, we show that glutamate dehydrogenase from viable cysts instructs tolerogenic monocytes to release IL-10 and the lipid mediator PGE 2 . These act in concert, converting naive CD4 + T cells into CD127 À CD25 hi FoxP3 + CTLA-4 + Tregs, through the G protein-coupled receptors EP2 and EP4 and the IL-10 receptor. Moreover, while viable cyst products strongly upregulate IL-10 and PGE 2 transcription in microglia, intravesicular fluid, released during cyst decay, induces pro-inflammatory microglia and TGF-b as potential drivers of epilepsy. Inhibition of PGE 2 synthesis and IL-10 signaling prevents Treg induction by viable cyst products. Harnessing the PGE 2 -IL-10 axis and targeting TGF-ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC.

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“…We speculate that the increase in cardiac Foxp3 mRNA levels, a transcription factor of T-regulatory cells may reflect a response to counteract the increase in Th17 cells. In an airway allergen-sensitive mouse model, PGI 2 signaling promoted differentiation of suppressive T regulatory cells via Fxop3 transcription factor to restrain immunoglobulin-like transcript 3 (ILT3) driven allergic inflammation (52).…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice

Tang¹,

Meng²,

Anderson³

et al. 2021

Journal of Clinical Investigation

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Inhibitors of mPges-1 are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing PGE 2 , but increasing biosynthesis of PGI 2 . In Ldlr -/mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE 2 accounts for its anti-atherogenic effect. However, the impact of mPges-1 depletion on BP in this setting remains unknown. Here, mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr -/mice, whereas, despite the direct vasodilator properties of PGI 2 , Ipr deletion suppressed it. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1 -/mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high salt diet. This is attributable to the protective effect of estrogen in Ldlr -/mice and in Ipr -/-/Ldlr -/mice. Thus, estrogen compensates for a deficiency in PGI 2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In males, by contrast, augmented formation of ANP plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hyperlipidemic males on a high salt diet might be at risk of a hypertensive response to mPGES-1 inhibitors.

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Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming

Cited by 13 publications

References 71 publications

Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation

Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation

Helminthic dehydrogenase drives PGE ₂ and IL‐10 production in monocytes to potentiate Treg induction

Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice

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Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming

Cited by 13 publications

References 71 publications

Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation

Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation

Helminthic dehydrogenase drives PGE 2 and IL‐10 production in monocytes to potentiate Treg induction

Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice

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Helminthic dehydrogenase drives PGE ₂ and IL‐10 production in monocytes to potentiate Treg induction