Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis.

Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl ß-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.

Apomorphine is a potent inhibitor of ferroptosis independent of dopaminergic receptors.

Originally, apomorphine was a broad-spectrum dopamine agonist with an affinity for all subtypes of the Dopamine D1 receptor to the D5 receptor. We previously identified apomorphine as a potential therapeutic agent for mitochondrial diseases by screening a chemical library of fibroblasts from patients with mitochondrial diseases. In this study, we showed that apomorphine prevented ferroptosis in fibroblasts from various types of mitochondrial diseases as well as in normal controls. Well-known biomarkers of ferroptosis include protein markers such as prostaglandin endoperoxide synthase 2 (PTGS2), a key gene for ferroptosis-related inflammation PTGS2, lipid peroxidation, and reactive oxygen species. Our findings that apomorphine induced significant downregulation of PTSG2 and suppressed lipid peroxide to the same extent as other inhibitors of ferroptosis also indicate that apomorphine suppresses ferroptosis. To our knowledge, this is the first study to report that the anti-ferroptosis effect of apomorphine is not related to dopamine receptor agonist action and that apomorphine is a potent inhibitor of ferroptotic cell death independent of dopaminergic receptors.

Isoliquiritigenin inhibits NLRP3 inflammasome activation with CAPS mutations by suppressing caspase-1 activation and mutated NLRP3 aggregation.

The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome contributes to the development of inflammatory diseases. Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by NLRP3 gene mutations that results in excessive IL-1ß production. We previously identified isoliquiritigenin (ILG), a component of Glycyrrhiza uralensis extracts, as a potent inhibitor of the NLRP3 inflammasome. Here, we aimed to investigate whether ILG inhibits the activation of NLRP3 inflammasome caused by NLRP3 gene mutations. We demonstrated that ILG significantly inhibited NLRP3 inflammasome-mediated lactate dehydrogenase (LDH) release and IL-1ß production in two CAPS model THP-1 cell lines, NLRP3-D303N and NLRP3-L353P, in a dose-dependent manner. Interestingly, the NLRP3 inhibitor MCC950 inhibited LDH release and IL-1ß production in NLRP3-D303N cells, but not in NLRP3-L353P cells. Western blotting and caspase-1 activity assays showed that ILG, as well as caspase inhibitors, including Z-VAD and YVAD, suppressed caspase-1 activation. Notably, ILG prevented cryo-sensitive foci formation of NLRP3 without affecting the levels of intracellular Ca2+. We concluded that ILG effectively prevents the constitutive activation of the inflammasome associated with NLRP3 gene mutations by inhibiting the aggregation of cryo-sensitive mutated NLRP3.

Gasdermin D regulates soluble fms-like tyrosine kinase 1 release in macrophages.

Preeclampsia (PE) is a serious complication, and soluble fms-like tyrosine kinase (sFLT1) released from the placenta is one of the causes of PE pathology. Trophoblasts are the primary source of sFLT1; however, monocytes/macrophages exist enough in the placenta can also secrete sFLT1. Sterile inflammatory responses, especially NLRP3 inflammasome and its downstream gasdermin D (GSDMD)-regulated pyroptosis, may be involved in the development of PE pathology. In this study, we investigated whether human monocyte/macrophage cell line THP-1 cells secrete sFLT1 depending on the NLRP3 inflammasome and GSDMD. To differentiate THP-1 monocytes into macrophages, treatment with phorbol 12-myristate 13-acetate (PMA) induced sFLT1 with interleukin (IL)- 1ß, but did not induce cell lytic death. IL-1ß secretion induced by PMA inhibited by deletion of NLRP3 and inhibitors of NLRP3 and caspase-1, but deletion of NLRP3 and these inhibitors did not affect sFLT1 secretion in THP-1 cells. Both gene deletion and inhibition of GSDMD dramatically decreased IL-1ß and sFLT1 secretion from THP-1 cells. Treatment with CA074-ME (a cathepsin B inhibitor) also reduced the secretion of both sFLT1 and IL-1ß in THP-1 cells. In conclusion, THP-1 macrophages release sFLT1 in a GSDMD-dependent manner, but not in the NLRP3 inflammasome-dependent manner, and this sFLT1 release may be associated with the non-lytic role of GSDMD. In addition, sFLT1 levels induced by PMA are associated with lysosomal cathepsin B in THP-1 macrophages. We suggest that sFLT1 synthesis regulated by GSDMD are involved in the pathology of PE.

Caspase-11 deficiency attenuates neutrophil recruitment into the atherosclerotic lesion in apolipoprotein E-deficient mice.

Caspase-11 is an inflammatory caspase that triggers an inflammatory response by regulating non-canonical NLRP3 inflammasome activation. Although the deficiency of both caspase-11 and caspase-1, another inflammatory caspase that functions as an executor of the inflammasome, prevents the development of atherosclerosis, the effect of caspase-11 deficiency alone on the development of atherosclerosis has not been fully evaluated. In the present study, we found that caspase-11 deficiency prevented the formation of the necrotic core, whereas it did not affect the development of atherosclerosis in Apoe-deficient mice. Notably, the infiltration of neutrophils into atherosclerotic lesions was attenuated by caspase-11 deficiency. RNA-seq analysis of stage-dependent expression of atherosclerotic lesions revealed that both upregulations of caspase-11 and neutrophil migration are common features of advanced atherosclerotic lesions. Furthermore, similar expression profiles were observed in unstable human plaque. These data suggest that caspase-11 regulates neutrophil recruitment and plaque destabilization in advanced atherosclerotic lesions.

Activation of the inflammasome drives peritoneal deterioration in a mouse model of peritoneal fibrosis.

During peritoneal dialysis (PD), the peritoneum is exposed to a bioincompatible dialysate, deteriorating the tissue and limiting the long-term effectiveness of PD. Peritoneal fibrosis is triggered by chronic inflammation induced by a variety of stimuli, including peritonitis. Exposure to PD fluid alters peritoneal macrophages phenotype. Inflammasome activation triggers chronic inflammation. First, it was determined whether inflammasome activation causes peritoneal deterioration. In the in vivo experiments, the increased expression of the inflammasome components, caspase-1 activity, and concomitant overproduction of IL-1ß and IL-18 were observed in a mouse model of peritoneal fibrosis. ASC-positive and F4/80-positive cells colocalized in the subperitoneal mesothelial cell layer. These macrophages expressed high CD44 levels indicating that the CD44-positive macrophages contribute to developing peritoneal deterioration. Furthermore, intravital imaging of the peritoneal microvasculature demonstrated that the circulating CD44-positive leukocytes may contribute to peritoneal fibrosis. Bone marrow transplantation in ASC-deficient mice suppressed inflammasome activation, thereby attenuating peritoneal fibrosis in a high glucose-based PD solution-injected mouse model. Our results suggest inflammasome activation in CD44-positive macrophages may be involved in developing peritoneal fibrosis. The inflammasome-derived pro-inflammatory cytokines might therefore serve as new biomarkers for developing encapsulating peritoneal sclerosis.

NLRP3 inflammasome-driven IL-1ß and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy.

Sepsis is a life-threatening syndrome, and its associated mortality is increased when cardiac dysfunction and damage (septic cardiomyopathy [SCM]) occur. Although inflammation is involved in the pathophysiology of SCM, the mechanism of how inflammation induces SCM in vivo has remained obscure. NLRP3 inflammasome is a critical component of the innate immune system that activates caspase-1 (Casp1) and causes the maturation of IL-1ß and IL-18 as well as the processing of gasdermin D (GSDMD). Here, we investigated the role of the NLRP3 inflammasome in a murine model of lipopolysaccharide (LPS)-induced SCM. LPS injection induced cardiac dysfunction, damage, and lethality, which was significantly prevented in NLRP3-/- mice, compared to wild-type (WT) mice. LPS injection upregulated mRNA levels of inflammatory cytokines (Il6, Tnfa, and Ifng) in the heart, liver, and spleen of WT mice, and this upregulation was prevented in NLRP3-/- mice. LPS injection increased plasma levels of inflammatory cytokines (IL-1ß, IL-18, and TNF-α) in WT mice, and this increase was markedly inhibited in NLRP3-/- mice. LPS-induced SCM was also prevented in Casp1/11-/- mice, but not in Casp11mt, IL-1ß-/-, IL-1α-/-, or GSDMD-/- mice. Notably, LPS-induced SCM was apparently prevented in IL-1ß-/- mice transduced with adeno-associated virus vector expressing IL-18 binding protein (IL-18BP). Furthermore, splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM. Our findings demonstrate that the cross-regulation of NLRP3 inflammasome-driven IL-1ß and IL-18 contributes to the pathophysiology of SCM and provide new insights into the mechanism underlying the pathogenesis of SCM.

A Myb enhancer-guided analysis of basophil and mast cell differentiation.

The transcription factor MYB is a crucial regulator of hematopoietic stem and progenitor cells. However, the nature of lineage-specific enhancer usage of the Myb gene is largely unknown. We identify the Myb -68 enhancer, a regulatory element which marks basophils and mast cells. Using the Myb -68 enhancer activity, we show a population of granulocyte-macrophage progenitors with higher potential to differentiate into basophils and mast cells. Single cell RNA-seq demonstrates the differentiation trajectory is continuous from progenitors to mature basophils in vivo, characterizes bone marrow cells with a gene signature of mast cells, and identifies LILRB4 as a surface marker of basophil maturation. Together, our study leads to a better understanding of how MYB expression is regulated in a lineage-associated manner, and also shows how a combination of lineage-related reporter mice and single-cell transcriptomics can overcome the rarity of target cells and enhance our understanding of gene expression programs that control cell differentiation in vivo.

dsDNA-induced AIM2 pyroptosis halts aberrant inflammation during rhabdomyolysis-induced acute kidney injury.

Rhabdomyolysis is a severe condition that commonly leads to acute kidney injury (AKI). While double-stranded DNA (dsDNA) released from injured muscle can be involved in its pathogenesis, the exact mechanism of how dsDNA contributes to rhabdomyolysis-induced AKI (RIAKI) remains obscure. A dsDNA sensor, absent in melanoma 2 (AIM2), forms an inflammasome and induces gasdermin D (GSDMD) cleavage resulting in inflammatory cell death known as pyroptosis. In this study using a mouse model of RIAKI, we found that Aim2-deficiency led to massive macrophage accumulation resulting in delayed functional recovery and perpetuating fibrosis in the kidney. While Aim2-deficiency compromised RIAKI-induced kidney macrophage pyroptosis, it unexpectedly accelerated aberrant inflammation as demonstrated by CXCR3+CD206+ macrophage accumulation and activation of TBK1-IRF3/NF-κB. Kidney macrophages with intact AIM2 underwent swift pyroptosis without IL-1ß release in response to dsDNA. On the other hand, dsDNA-induced Aim2-deficient macrophages escaped from swift pyroptotic elimination and instead engaged STING-TBK1-IRF3/NF-κB signalling, leading to aggravated inflammatory phenotypes. Collectively, these findings shed light on a hitherto unknown immunoregulatory function of macrophage pyroptosis. dsDNA-induced rapid macrophage cell death potentially serves as an anti-inflammatory program and determines the healing process of RIAKI.

Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3 gene encoding cryopyrin. Familial cold autoinflammatory syndrome, the mildest form of CAPS, is characterized by cold-induced inflammation induced by the overproduction of IL-1ß. However, the molecular mechanism of how mutated NLRP3 causes inflammasome activation in CAPS remains unclear. Here, we found that CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function as a scaffold for inflammasome activation. Cold exposure promoted inflammasome assembly and subsequent IL-1ß release triggered by mutated NLRP3. While K+ efflux was dispensable, Ca2+ was necessary for mutated NLRP3-mediated inflammasome assembly. Notably, Ca2+ influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca2+ influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca2+ influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation.

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

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)-1ß 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-1ß 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-1ß 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.

NLRP3 inflammasome as a key driver of vascular disease.

Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) is an intracellular innate immune receptor that recognizes a diverse range of stimuli derived from pathogens, damaged or dead cells, and irritants. NLRP3 activation causes the assembly of a large multiprotein complex termed the NLRP3 inflammasome, and leads to the secretion of bioactive interleukin (IL)-1ß and IL-18 as well as the induction of inflammatory cell death termed pyroptosis. Accumulating evidence indicates that NLRP3 inflammasome plays a key role in the pathogenesis of sterile inflammatory diseases, including atherosclerosis and other vascular diseases. Indeed, the results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study trial demonstrated that IL-1ß-mediated inflammation plays an important role in atherothrombotic events and suggested that NLRP3 inflammasome is a key driver of atherosclerosis. In this review, we will summarize the current state of knowledge regarding the role of NLRP3 inflammasome in vascular diseases, in particular in atherosclerosis, vascular injury, aortic aneurysm, and Kawasaki disease vasculitis, and discuss NLRP3 inflammasome as a therapeutic target for these disorders.

Elevated S100A9 in preeclampsia induces soluble endoglin and IL-1ß secretion and hypertension via the NLRP3 inflammasome.

OBJECTIVES: Maternal systemic and placental inflammatory responses participate in the pathogenesis of hypertensive disorders of pregnancy including preeclampsia, a pregnancy-specific syndrome, although the role of inflammation remains unclear. The NLRP3 inflammasome has been implicated in the control of sterile inflammation involved in preeclampsia. In the present study, we hypothesized that S100A9, as major alarmin, are associated with the pathogenesis of preeclampsia and induction of a preeclampsia-like phenotype in pregnant mice. METHODS: Plasma were taken from normal pregnant women and preeclampsia patients. Human placental tissues, trophoblast cell line Sw.71 cells, and human umbilical vein endothelial cells (HUVEC) were treated with S100A9 with or without inhibitors associated with NLRP3 inflammasome. Pregnant mice were administered S100A9. RESULTS: S100A9 was elevated in plasma and released from placentas of preeclampsia patients. S100A9 activated the NLRP3 inflammasome, resulting in IL-1ß secretion, by human placental tissues and trophoblasts. In addition, secretion of soluble endoglin, a main contributor to the pathogenesis of preeclampsia, is regulated via S100A9-stimulated NLRP3 inflammasome activation in the human placenta and HUVECs. S100A9 administration significantly elevated maternal blood pressure and neutrophil accumulation within the placentas of pregnant mice, and both were significantly decreased in Nlrp3-knock out pregnant mice. CONCLUSION: The results of this study demonstrated that S100A9 acts as a danger signal to activate the NLRP3 inflammasome in the placenta, associating with hypertension during pregnancy.

Loop Between NLRP3 Inflammasome and Reactive Oxygen Species.

Significance: Inflammasomes are cytosolic multiprotein complexes that mediate innate immune pathways. Inflammasomes activate inflammatory caspases and regulate inflammatory cytokines interleukin (IL)-1ß and IL-18 as well as inflammatory cell death (pyroptosis). Among known inflammasomes, NLRP3 (NLR family pyrin domain containing 3) inflammasome is unique and well studied owing to the fact that it senses a broad range of stimuli and is implicated in the pathogenesis of both microbial and sterile inflammatory diseases. Recent Advances: Reactive oxygen species (ROS), especially derived from the mitochondria, are one of the critical mediators of NLRP3 inflammasome activation. Furthermore, NLRP3 inflammasome-driven inflammation recruits inflammatory cells, including macrophages and neutrophils, which in turn cause ROS production, suggesting a feedback loop between ROS and NLRP3 inflammasome. Critical Issues: The precise mechanism of how ROS affects NLRP3 inflammasome activation still need to be addressed. This review will summarize the current knowledge on the molecular mechanisms underlying the activation of NLRP3 inflammasome with particular emphasis on the intricate balance of feedback loop between ROS and inflammasome activation. Future Directions: Understanding that this relationship is loop rather than traditionally understood linear mechanism will enable to fine-tune inflammasome activation under varied pathological settings. Antioxid. Redox Signal. 36, 784-796.

Satisfied quantitative value can be acquired by short-time bone SPECT/CT using a whole-body cadmium-zinc-telluride gamma camera.

The aim of this study was to evaluate the quantitative values of short-time scan (STS) of metastatic lesions compared with a standard scan (SS) when acquired by whole-body bone SPECT/CT with cadmium-zinc-telluride (CZT) detectors. We retrospectively reviewed 13 patients with bone metastases from prostate cancer, who underwent SPECT/CT performed on whole-body CZT gamma cameras. STSs were obtained using 75, 50, 25, 10, and 5% of the list-mode data for SS, respectively. Regions of interest (ROIs) were set on the increased uptake areas diagnosed as metastases. Intraclass correlation coefficients (ICCs) of standardized uptake values (SUVs) for the ROIs were calculated between the SS and each STS, and ICC ≥ 0.8 was set as a perfect correlation. Moreover, the repeatability coefficient (RC) was calculated, and RC ≤ 20% was defined as acceptable. A total of 152 metastatic lesions were included in the analysis. The ICCs between the SS vs. 75%-STS, 50%-STS, 25%-STS, 10%-STS, and 5%-STS were 0.999, 0.997, 0.994, 0.983, and 0.955, respectively. The RCs of the SS vs. 75%-STS, 50%-STS, 25%-STS, 10%-STS, and 5%-STS were 7.9, 12.4, 19.8, 30.8, and 41.3%, respectively. When evaluating the quality of CZT bone SPECT/CT acquired by a standard protocol, 25%-STS may provide adequate quantitative values.

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

The immune system contributes to the regulation of pregnancy, and the disruption of well-controlled immune functions leads to pregnancy complications. Recently, the nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome mechanisms [(a protein complex of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1)] have been reported to play roles in controlling placental inflammation involved in pregnancy pathologies. The ketone body ß-hydroxybutyrate (BHB) can suppress NLRP3 inflammasome activation and improve various inflammatory diseases. Therefore, we hypothesized that BHB could suppress activation of the NLRP3 inflammasome in the placenta, resulting in the improvement of pregnancy complications. In human placental tissue culture, treatment with BHB suppressed the secretion levels of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and IL-8, but did not affect the mRNA expression levels of NLRP3 inflammasome-associated factors. Treatment with BHB reduced IL-1ß secretion and the amount of mature IL-1ß protein induced by lipopolysaccharide (LPS) stimulation in the placenta. In human trophoblast cells, BHB reduced ASC and activated-caspase-1 expression, resulting in the inhibition of IL-1ß secretion. To investigate the effect of BHB during pregnancy, we used an animal model of LPS (100 µg/kg intraperitoneally [i.p.] on gestational day 14)-induced pregnancy complications. Administration of BHB (100 mg/kg i.p.) clearly suppressed the absorption rate and IL-1ß production in the placenta induced by LPS in pregnant mice. Moreover, LPS-induced pregnancy abnormalities were improved in NLRP3-deficient mice. These findings suggest that BHB play a role in reducing placental inflammation and pregnancy complications via inhibition of NLRP3 inflammasome activation.

Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation.

Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17-19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.

Rare Contents of an Internal Hernia through a Defect of the Broad Ligament of the Uterus.

Herniation through a defect of the uterine broad ligament is a rare internal hernia that is difficult to diagnose definitively. Common hernia contents contain ileal loops. Herein, we report a rare case of internal herniation of both the ileum and fallopian tube through a defect of the broad ligament. A 52-year-old woman presented to our hospital with suprapubic pain and vomiting. She had a history of bowel obstruction following cesarean section. On abdominopelvic computed tomography, we suspected a closed-loop obstruction associated with bowel herniation in the right broad ligament. However, we could not identify an area of poor enhancement adjacent to distended small intestines. Emergency laparoscopic exploration revealed a viable ileal loop and incarcerated organ. Therefore, we switched to laparotomy that revealed the right fallopian tube as the ischemic organ. We reduced the hernia, resected necrotic right fallopian tube, and closed the defect of the broad ligament. The patient had an uneventful postoperative course. Rare hernia contents might complicate preoperative clinical diagnosis. Laparoscopy is useful for establishing a definitive diagnosis and treating broad ligament hernias.

Calciprotein Particles Induce IL-1ß/α-Mediated Inflammation through NLRP3 Inflammasome-Dependent and -Independent Mechanisms.

Calciprotein particles (CPPs) are nanoparticles composed of calcium phosphate crystals and fetuin-A and have been implicated in diseases associated with inflammation. In the current study, we investigated the molecular mechanisms underlying CPP-induced inflammation in mice. CPPs predominantly upregulated IL-1ß and IL-1α and provided priming and activation signals for the NLRP3 inflammasome in murine macrophages. Pharmacological and genetic inhibition of the NLRP3 inflammasome revealed that CPPs induced the release of IL-1ß and IL-1α via NLRP3 inflammasome-dependent and -independent mechanisms, respectively. CPPs also induced necrotic cell death, but gasdermin D was dispensable for CPP-induced IL-1ß release and necrotic cell death. Although phagocytosis of CPPs was required for CPP-induced IL-1ß/α release and necrotic cell death, lysosomal dysfunction and K+ efflux were mainly involved in CPP-induced NLRP3 inflammasome activation and subsequent IL-1ß release but not in CPP-induced IL-1α release and necrotic cell death. In vivo experiments showed that CPP administration evoked acute inflammatory responses characterized by neutrophil accumulation via both IL-1ß and IL-1α. In particular, CPP-induced neutrophil inflammation was mediated predominantly through an IL-1α-induced CXCL1/CXCR2 signaling pathway. These results provide new insights into the mechanism underlying CPP-induced inflammation and suggest that targeting both IL-1ß and IL-1α is necessary to regulate the CPP-induced inflammatory response and to treat CPP-associated inflammatory disorders.

NLRP3 Inflammasome as a Common Denominator of Atherosclerosis and Abdominal Aortic Aneurysm.

Atherosclerosis and abdominal aortic aneurysm (AAA) are multifactorial diseases characterized by inflammatory cell infiltration, matrix degradation, and thrombosis in the arterial wall. Although there are some differences between atherosclerosis and AAA, inflammation is a prominent common feature of these disorders. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic multiprotein complex that activates caspase-1 and regulates the release of proinflammatory cytokines interleukin (IL)-1ß and IL-18, as well as the induction of lytic cell death, termed pyroptosis, thereby leading to inflammation. Previous experimental and clinical studies have demonstrated that inflammation in atherosclerosis and AAA is mediated primarily through the NLRP3 inflammasome. Furthermore, recent results of the Canakinumab Anti-inflammatory Thrombosis and Outcome Study (CANTOS) showed that IL-1ß inhibition reduces systemic inflammation and prevents atherothrombotic events; this supports the concept that the NLRP3 inflammasome is a promising therapeutic target for cardiovascular diseases, including atherosclerosis and AAA. This review summarizes current knowledge with a focus on the role of the NLRP3 inflammasome in atherosclerosis and AAA, and discusses the prospects of NLRP3 inflammasome-targeted therapy.