IL-1β Production through the NLRP3 Inflammasome by Hepatic Macrophages Links Hepatitis C Virus Infection with Liver Inflammation and Disease

Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease. Liver inflammation underlies infection-induced fibrosis, cirrhosis and liver cancer but the processes that promote hepatic inflammation by HCV are not defined. We provide a systems biology analysis with multiple lines of evidence to indicate that interleukin-1β (IL-1β) production by intrahepatic macrophages confers liver inflammation through HCV-induced inflammasome signaling. Chronic hepatitis C patients exhibited elevated levels of serum IL-1β compared to healthy controls. Immunohistochemical analysis of healthy control and chronic hepatitis C liver sections revealed that Kupffer cells, resident hepatic macrophages, are the primary cellular source of hepatic IL-1β during HCV infection. Accordingly, we found that both blood monocyte-derived primary human macrophages, and Kupffer cells recovered from normal donor liver, produce IL-1β after HCV exposure. Using the THP-1 macrophage cell-culture model, we found that HCV drives a rapid but transient caspase-1 activation to stimulate IL-1β secretion. HCV can enter macrophages through non-CD81 mediated phagocytic uptake that is independent of productive infection. Viral RNA triggers MyD88-mediated TLR7 signaling to induce IL-1β mRNA expression. HCV uptake concomitantly induces a potassium efflux that activates the NLRP3 inflammasome for IL-1β processing and secretion. RNA sequencing analysis comparing THP1 cells and chronic hepatitis C patient liver demonstrates that viral engagement of the NLRP3 inflammasome stimulates IL-1β production to drive proinflammatory cytokine, chemokine, and immune-regulatory gene expression networks linked with HCV disease severity. These studies identify intrahepatic IL-1β production as a central feature of liver inflammation during HCV infection. Thus, strategies to suppress NLRP3 or IL-1β activity could offer therapeutic actions to reduce hepatic inflammation and mitigate disease.     

Collagen abundance in mechanically stimulated osteoblast cultures using near infrared microscopy

Collagen abundance in osteoblast cell cultures was determined using near infrared microscopy with chemical imaging (NIR-CI) with and without mechanical stimulation of the the cells. MC3T3-E1 mouse osteoblast cells seeded on a polycarbonate substrate were mechanically stimulated using static loads of 13.5 N, 27 N and 40 N applied to the substrates during 2, 4, 6 and 8 days of incubation. Results show that the cells increased their collagen production with 13.5 N and 27 N loads when compared to the control sample with a 27 N load resulting in a noteworthy increase (109%) in collagen production. The 40 N load on the other hand, resulted in an initial decrease in the collagen expression in the extracellular matrix, possibly as a result of cell death or inhibition of the protein secretion process followed by an increase in collagen after cell recovery and proliferation. Qualitative confirmation of these results was performed using confocal microscopy.     

Virus dynamics in a large epishelf lake (Beaver Lake,Antarctica)

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Post-cardiac injury syndrome in acute myocardial infarction patients undergoing PCI: a case report and literature review

Background

In the era of primary percutaneous coronary intervention (PPCI), the incidence of post-cardiac injury syndrome (PCIS) in patients with acute myocardial infarction (AMI) following PPCI has become less common. However, the intrinsic pathogenesis of this medical condition remains largely uncertain. Unlike the prior reports, the present paper provides new mechanistic clues concerning the pathogenesis of PCI-related PCIS.

Case presentation

A 45-year-old male with AMI had developed an early onset of PCIS at 3?h after PPCI. A significantly slower TIMI flow (grade ≤?2) for the culprit arteries was observed through follow-up coronary angiography (CAG); no stent thrombosis or any significant evidence of iatrogenic trauma due the intervention procedures was found. Nevertheless, the the serum level of HsCRP showed similar variation trend as the neutrophil count and troponin T in continuous blood monitoring, which suggested a potential association between PPCI-related coronary microvascular dysfunction (CMD) and pathogenesis of PCIS.

Conclusions

The reported case had excessive inflammatory reaction and CMD resulting from cardiac ischemia-reperfusion injury in an AMI patient with risk factors of endothelial dysfunction. There exists a potential reciprocal causation between PCIS and performance of PPCI in the AMI patient who was susceptible to endothelial damage.

     

Structures of Hsp90α and Hsp90β bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity

Hsp90α and Hsp90β are implicated in a number of cancers and neurodegenerative disorders but the lack of selective pharmacological probes confounds efforts to identify their individual roles. Here, we analyzed the binding of an Hsp90α-selective PU compound, PU-11-trans, to the two cytosolic paralogs. We determined the co-crystal structures of Hsp90α and Hsp90β bound to PU-11-trans, as well as the structure of the apo Hsp90β NTD. The two inhibitor-bound structures reveal that Ser52, a nonconserved residue in the ATP binding pocket in Hsp90α, provides additional stability to PU-11-trans through a water-mediated hydrogen-bonding network. Mutation of Ser52 to alanine, as found in Hsp90β, alters the dissociation constant of Hsp90α for PU-11-trans to match that of Hsp90β. Our results provide a structural explanation for the binding preference of PU inhibitors for Hsp90α and demonstrate that the single nonconserved residue in the ATP-binding pocket may be exploited for α/β selectivity.     

Jun kinase delays caspase-9 activation by interaction with the apoptosome

Activation of c-Jun N-terminal kinase 1/2 (JNK) can delay oxidant-induced cell death, but the mechanism is unknown. We found that oxidant stress of cardiac myocytes activated both JNK and mitochondria-dependent apoptosis and that expression of JNK inhibitory mutants accelerated multiple steps in this pathway, including the cleavage and activation of caspases-3 and -9 and DNA internucleosomal cleavage, without affecting the rate of cytochrome c release; JNK inhibition also increased caspase-3 and -9 cleavage in a cell-free system. On activation by GSNO or H(2)O(2), JNK formed a stable association with oligomeric Apaf-1 in a approximately 1.4-2.0 mDa pre-apoptosome complex. Formation of this complex could be triggered by addition of cytochrome c and ATP to the cell-free cytosol. JNK inhibition abrogated JNK-Apaf-1 association and accelerated the association of procaspase-9 and Apaf-1 in both intact cells and cell-free extracts. We conclude that oxidant-activated JNK associates with Apaf-1 and cytochrome c in a catalytically inactive complex. We propose that this interaction delays formation of the active apoptosome, promoting cell survival during short bursts of oxidative stress.     

Intra- and extragenic marker haplotypes of CFTR mutations in cystic fibrosis families

Summary In order to facilitate the screening for the less common mutations in the cystic fibrosis (CF) gene viz., the CF transmembrane conductance regulator gene (CFTR), marker haplotypes were determined for German nonCF (N) and CF chromosomes by polymerase chain reaction analysis of four polymorphisms upstream of the CF gene (XV-2c, KM.19, MP6-D9, J44) and six intragenic polymorphisms (GATT, TUB9, M470V, T854T, TUB18, TUB20) that span the CFTR gene from exon 6 through exon 21. Novel informative sequence variants of CFTR were detected in front of exons 10 (1525-61 A or G), 19 (3601-65 C or A), and 21 (4006-200 A or G). The CF locus exhibits strong long-range marker-marker linkage disequilibrium with breakpoints of recombination between XV-2c and KM.19, and between exons 10 and 19 of CFTR. Marker alleles of GATT-TUB9 and TUB18-TUB20 were found to be in absolute linkage disequilibrium. Four major haplotypes encompass more than 90% of German N and CF chromosomes. Fifteen CFTR mutations detected on 421 out of 500 CF chromosomes were each identified on one of these four predominant 7-marker haplotypes. Whereas all analysed F508 chromosomes carried the same KM.19-D9-J44-GATT-TUB9-M470V-T854T haplotype, another frequent mutation in Germany, R553X, was identified on two different major haplotypes. Hence, a priori haplotyping cannot exclude a particular CF mutation, but in combination with population genetic data, enables mutations to be ranked by decreasing probability.     

A termination mutation (2143delT) in the CFTR gene of German cystic fibrosis patients

German patients with cystic fibrosis (CF) were screened for molecular lesions in exon 13 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by single strand conformation polymorphism (SSCP) and chemical cleavage of mismatch analyses. Direct sequencing of four samples that displayed the same SSCP pattern and that were susceptible to cleavage of heteroduplexes by osmium tetroxide revealed, in all cases, a deletion of a single T residue at nucleotide position 2143 within codon 671 of the CFTR gene. As a result, leucine codon 671 is changed into a termination codon. In total, the 2143delT mutation was confirmed in 6 out of 271 German non-F508 CF chromosomes by artificial restriction fragment length polymorphism analysis, indicating that this frameshift mutation accounts for about 2% of German non-508 mutations. The 6 pancreas insufficient patients who are compound heterozygous for 2143-delT suffer from the typical features of pulmonary and gastrointestinal CF disease. The 2143delT mutation completes the panel of the more frequent CFTR mutations that reside on the F508 haplotype and that contribute to its overpresentation among German non-F508 alleles that are associated with severe forms of disease.     

A Comparison of Health Complaints of Settled and Nomadic Turkana Men

This article examines the health complaints of settled and nomadic Ngisonyoka Turkana of northwest Kenya. Samples of 152 nomadic and 124 settled men, aged 14 and over, were surveyed about their health status. The general pattern of disease reported concurs with previous studies of health among Turkana; that is, the primary complaints are respiratory tract infections and eye infections. The settled Turkana reported more severe complaints and higher rates of infectious disease than the nomads, including a significantly higher frequency of cold with cough, eye infection, and chest infection. Although the settled males as a group had slightly higher body mass index and other measures of body fat than the nomadic group, none of these indicators of body composition were predictive of health complaints. Observed differences in health patterns are possibly related to differences in dietary composition, exposure to pathogens associated with population density and environmental pollution, physical activity patterns, and psychosocial stress.