β-hydroxybutyrate suppresses NLRP3 inflammasome-mediated placental inflammation and lipopolysaccharide-induced fetal absorption

Hirata, Yoshiki; Shimazaki, Sayaka; Suzuki, Seiya; Henmi, Yuka; Komiyama, Hiromu; Kuwayama, Takehito; Iwata, Hisataka; Karasawa, Tadayoshi; Takahashi, Masafumi; Takahashi, Hironori; Shirasuna, Koumei

doi:10.1016/j.jri.2021.103433

Cited by 15 publications

(14 citation statements)

References 49 publications

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“…Building on this, our study is the first to demonstrate a similarly increased expression for NLRP3 in the placentae from FGR-affected pregnancies. Hence, reducing NLRP3 activation may be a therapeutic target for FGR, given that other studies demonstrate the utility of inhibiting NLRP3 activation using β-hydroxybutyrate and the specific inhibitor MCC950, to reduce NLRP3 inflammasome-mediated preterm birth and fetal death in various animal models [35,58].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, in this study, the spatial distribution of candidate inflammasome proteins in the placentae obtained from Balb/c mice at E18, following LPS-induced inflammation, was investigated. A model of LPS with subclinical infection was included as placental inflammation and elevated DAMPs frequently detected, despite no clinical signs of infection [34,35]. Briefly, pregnant Balb/c mice housed under conventional conditions, had ad libitium access to food and water, and were maintained in a 12 h light-12 h dark cycle.…”

Section: Placental Nlrp3 Expression In An Inflammation-induced Murine...mentioning

confidence: 99%

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The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

Alfian

Chakraborty

Yong

et al. 2022

Cells

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Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (<2-fold) in FGR compared with control pregnancies. LPS treatment increased NLRP3 and caspase-1 expression (>2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.

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Section: Discussionmentioning

confidence: 99%

Section: Placental Nlrp3 Expression In An Inflammation-induced Murine...mentioning

confidence: 99%

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

Alfian

Chakraborty

Yong

et al. 2022

Cells

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“…On the other hand, although LPS temporarily diminished testosterone levels at 12–24 h after injection, testosterone levels returned to its normal level after 72 h of LPS administration 7 . It is well known that peritoneal administration of LPS induced a systemic inflammatory response including the liver, spleen, and testis 5,7,27 . It is unclear whether LPS directly flows into the testis and affects it, or whether LPS‐induced inflammatory cytokines affect it.…”

Section: Discussionmentioning

confidence: 99%

“…7 It is well known that peritoneal administration of LPS induced a systemic inflammatory response including the liver, spleen, and testis. 5,7,27 It is unclear whether LPS directly flows into the testis and affects it, or whether LPS-induced inflammatory cytokines affect it. Interestingly, Wang et al 7 reported that the direct injection of LPS into the testis dramatically induced testicular dysfunction in mice.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome is involved in testicular inflammation induced by lipopolysaccharide in mice

Sano

Komiyama

Shinoda

et al. 2022

American J Rep Immunol

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Problem Systemic inflammation induced by infection, which is associated with testicular inflammation, predisposes males to subfertility. Recently, the nucleotide‐binding oligomerization domain, leucine‐rich repeat‐, and pyrin domain‐containing 3 (NLRP3) inflammasome was identified as a key mediator of inflammation, and excessive activation of the NLRP3 inflammasome was shown to contribute to the pathogenesis of a wide variety of diseases. However, the mechanisms underlying infectious inflammation in the testis remain unclear. We investigated the effect of lipopolysaccharide (LPS)‐induced systemic inflammation on the role of the NLRP3 inflammasome in murine testes. Method of study We performed in vivo and in vitro studies using an LPS‐induced model of NLRP3 inflammasome activation and testicular inflammation. Results Intraperitoneal administration of LPS significantly impaired sperm motility in the epididymis of wild type (WT) and NLRP3‐knockout (KO) mice. LPS administration stimulated interleukin (IL)‐1β production and secretion in the testes of WT mice, and these adverse effects were improved in the testes of NLRP3‐KO mice. LPS administration also stimulated neutrophil infiltration as well as its chemoattractant C‐C motif chemokine ligand 2 (CCL2) in WT testes, which were suppressed in NLRP3‐KO testes. In in vitro cell culture, treatment with LPS and NLRP3 inflammasome activation significantly induced IL‐1β and CCL2 secretion from WT but not NLRP3‐KO testicular cells. Conclusions Taken together, our results suggest that testicular cells have the potential to secrete IL‐1β and CCL2 in an NLRP3 inflammasome‐dependent manner and that these cytokines from the testis may further exacerbate testicular function, resulting in subfertility during infectious diseases.

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“…Consistent with this, bacterial LPS stimulation induced trophoblastic NLRP3 inflammasome activation and fetal absorption, and TANK-binding kinase 1 (TBK1) inhibition attenuated NLRP3 inflammasome activation by targeting the mammalian target of rapamycin complex 1 (mTORC1) ( 38 , 39 ). Moreover, LPS-induced pregnancy abnormalities were improved in NLRP3-deficient mice ( 40 ). These findings suggest that this innate immune complex could play a key role in placental immune defense.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 mediates trophoblastic inflammasome activation and protects against Listeria monocytogenes infection during pregnancy

Gao¹,

Zhou²,

Zhang³

et al. 2022

Ann Transl Med

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Background: Intrauterine Listeria monocytogenes (L. monocytogenes) infections pose a major threat during pregnancy via affecting placental immune responses. However, the underlying mechanisms of placental defense against this pathogen remain ill-defined. Therefore, this study aims to investigate the function and the mechanism of inflammasomes on against L. monocytogenes infection during pregnancy.Methods: A listeriosis murine model and cell culture system was used to investigate the role of trophoblastic nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) in orchestrating innate immune responses to L. monocytogenes infection. Caspase-1 activity was determined using a caspase-1 activity colorimetric kit. NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) in placental tissue was detected by immunohistochemistry. NLRP3 in HTR-8/SVneo cells was also detected by immunofluorescence. The expression of interleukin 1β (IL-1β), NLRP3, ASC, and caspase-1 was detected by Western blot. We characterized the NLRP3 inflammasome in trophoblast cells according to whether L. monocytogenes infection increased the activation of caspase-1 and the release of IL-1β. For human or mouse IL-1β in the culture supernatants and mouse tissue lysates were analyzed using ELISA Kits.Results: Trophoblast cells constitutively expressed the components of the NLRP3 inflammasome. In vitro, L. monocytogenes triggers NLRP3 inflammasome activation in trophoblast cells by inducing caspase-1 activation, increasing the NLRP3 protein levels, IL-1β maturation and secretion in HTR-8/SVneo cells. In vivo, L. monocytogenes induces fetal resorption and IL-1β processing in pregnant mice. In addition, NLRP3-deficient mice were more prone to fetal loss than their wild-type counterparts following infection with L. monocytogenes at a lower infective dose. Conclusions:We conclude that trophoblast cells respond to L. monocytogenes infection through the NLRP3 receptor, resulting in inflammasome activation and IL-1β production, which prevents listeriosis during pregnancy.

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β-hydroxybutyrate suppresses NLRP3 inflammasome-mediated placental inflammation and lipopolysaccharide-induced fetal absorption

Cited by 15 publications

References 49 publications

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

NLRP3 inflammasome is involved in testicular inflammation induced by lipopolysaccharide in mice

NLRP3 mediates trophoblastic inflammasome activation and protects against Listeria monocytogenes infection during pregnancy

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