Summary
Acinetobacter baumannii is a multi‐drug resistant, Gram‐negative bacteria and infection with this organism is one of the major causes of mortality in intensive care units. Inflammasomes are ...multiprotein oligomers that include caspase‐1, and their activation is required for maturation of interleukin‐1β (IL‐1β). Inflammasome signalling is involved in host defences against various microbial infections, but the precise mechanism by which A. baumannii activates inflammasomes and the roles of relevant signals in host defence against pulmonary A. baumannii infection are unknown. Our results showed that NLRP3, ASC and caspase‐1, but not NLRC4, are required for A. baumannii‐induced production of IL‐1β in macrophages. An inhibitor assay revealed that various pathways, including P2X7R, K+ efflux, reactive oxygen species production and release of cathepsins, are involved in IL‐1β production in macrophages in response to A. baumannii. Interleukin‐1β production in bronchoalveolar lavage (BAL) fluid was impaired in NLRP3‐deficient and caspase‐1/11‐deficient mice infected with A. baumannii, compared with that in wild‐type (WT) mice. However, the bacterial loads in BAL fluid and lungs were comparable between WT and NLRP3‐deficient or caspase‐1/11‐deficient mice. The severity of lung pathology was reduced in NLRP3‐ deficient, caspase‐1/11‐ deficient and IL‐1‐receptor‐deficient mice, although the recruitment of immune cells and production of inflammatory cytokines and chemokines were not altered in these mice. These findings indicate that A. baumannii leads to the activation of NLRP3 inflammasome, which mediates IL‐1β production and lung pathology.
NLRP3/ASC/caspase‐1 axis mediates IL‐1β production in response to Acinetobacter baumannii NLRP3 inflammasome and IL‐1β contribute to A. baumannii‐induced lung pathology.
Background: The impact of meeting leisure-time physical activity (LTPA) recommendations and household physical activity (HPA) on all-cause mortality in the Taiwanese population is unclear. We aimed ...to investigate the relationship between sufficient LTPA and all-cause mortality in middle-aged and older Taiwanese adults and the role of HPA in those with insufficient LTPA.Methods: This nationwide prospective cohort study included 4,960 participants aged ≥50 years from the Taiwan Longitudinal Study in Aging (TLSA) survey. Physical activity patterns were assessed in 2003 and then followed up until 2015 for mortality through the National Death Registration Record. Cox proportional hazards regression was conducted to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality.Results: Of the 4,960 participants, 1,712 died of all-cause mortality. Compared to those who had insufficient LTPA, participants who engaged in sufficient LTPA showed a significantly lower risk of all-cause mortality (HR = 0.84, 95% CI, 0.73–0.97). For those with insufficient LTPA, HPA also had a significantly reduced risk of all-cause mortality (HR = 0.85, 95% CI, 0.75–0.96) among general population. Similar associations were observed in subsequent sensitivity analyses. The subgroup analysis showed that the relationship between HPA and reduced mortality risk was only found in the women with insufficient LTPA group.Conclusion: This study confirmed that sufficient LTPA is associated with a lower risk of all-cause mortality. If sufficient LTPA cannot be performed, additional HPA is related to lower mortality.
WAP 4-disulfide core domain protein 2 (WFDC2), also known as human epididymis protein 4, is a small secretory protein that is highly expressed in fibrosis and human cancers, particularly in the ...ovaries, lungs, and stomach. However, the role of WFDC2 in carcinogenesis is not fully understood. The present study aimed to investigate the role of WFDC2 in gastric carcinogenesis with the use of preneoplastic metaplasia models.
Three spasmolytic polypeptide–expressing metaplasia (SPEM) models were established in both wild-type and Wfdc2-knockout mice with DMP-777, L635, and high-dose tamoxifen, respectively. To reveal the functional role of WFDC2, we performed transcriptomic analysis with DMP-777–treated gastric corpus specimens.
Wfdc2-knockout mice exhibited remarkable resistance against oxyntic atrophy, SPEM emergence, and accumulation of M2-type macrophages in all 3 SPEM models. Transcriptomic analysis revealed that Wfdc2-knockout prevented the up-regulation of interleukin-33 (IL33) expression in the injured mucosal region of SPEM models. Notably, supplementation of recombinant WFDC2 induced IL33 production and M2 macrophage polarization, and ultimately promoted SPEM development. Moreover, long-term treatment with recombinant WFDC2 was able to induce SPEM development.
WFDC2 expressed in response to gastric injury promotes SPEM through the up-regulation of IL33 expression. These findings provide novel insights into the role of WFDC2 in gastric carcinogenesis.
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Cryopyrin is essential for caspase-1 activation triggered by Toll-like receptor (TLR) ligands in the presence of adenosine triphosphate (ATP). However, the events linking bacterial products and ATP ...to cryopyrin remain unclear. Here we demonstrate that cryopyrin-mediated caspase-1 activation proceeds independently of TLR signaling, thus dissociating caspase-1 activation and IL-1β secretion. Instead, caspase-1 activation required pannexin-1, a hemichannel protein that interacts with the P2X
7 receptor. Direct cytosolic delivery of multiple bacterial products including lipopolysaccharide, but not flagellin, induced caspase-1 activation via cryopyrin in the absence of pannexin-1 activity or ATP stimulation. However, unlike Ipaf-dependent caspase-1 activation, stimulation of the pannexin-1-cryopyrin pathway by several intracellular bacteria was independent of a functional bacterial type III secretion system. These results provide evidence for cytosolic delivery and sensing of bacterial molecules as a unifying model for caspase-1 activation and position pannexin-1 as a mechanistic link between bacterial stimuli and the cryopyrin inflammasome.
The cytosolic sensors Nod1 and Nod2 and Toll-like receptors (TLRs) activate defense signaling pathways in response to microbial stimuli. However, the role of Nod1 and Nod2 and their interplay with ...TLRs during systemic bacterial infection remains poorly understood. Here, we report that macrophages or mice made insensitive to TLRs by previous exposure to microbial ligands remained responsive to Nod1 and Nod2 stimulation. Furthermore, Nod1- and Nod2-mediated signaling and gene expression are enhanced in TLR-tolerant macrophages. Further analyses revealed that innate immune responses induced by bacterial infection relied on Nod1 and Nod2 and their adaptor RICK in macrophages pretreated with TLR ligands but not in naive macrophages. In addition, bacterial clearance upon systemic infection with L. monocytogenes was critically dependent on Nod1 and Nod2 when mice were previously stimulated with lipopolysaccharide or E. coli. Thus, Nod1 and Nod2 are important for microbial recognition and host defense after TLR stimulation.
Phase angle (PhA) is an indicator of cellular health and is positively associated with overall physical activity (PA). However, varied associations between different intensities of PA and PhA by body ...segment in older populations remain unexplored. We investigated the associations between overall and different intensities of PA and upper-, lower-, and whole-body PhA in older adults. Overall exposure to light-intensity (LPA), moderate-intensity (MPA), and vigorous-intensity physical activity (VPA) was assessed using a triaxial accelerometer (GT3X + , ActiGraph). The outcome variables were upper-, lower-, and whole-body PhA measured using bioelectrical impedance analysis (MC-780MA, TANITA). Multiple linear regression helped examine the associations between the exposure and outcome variables after adjusting for age, gender, body mass index, and accelerometer wear time. A cross-sectional analysis involved 166 community-dwelling older participants (mean age = 72.1 ± 5.5 years; 78.3% women). Overall PA was associated with larger upper- (B: 0.057, 95% confidence interval CI 0.018-0.095) and whole-body PhA (B: 0.044, 95% CI 0.006-0.081). LPA was associated with larger upper-body PhA (B: 0.059, 95% CI 0.017-0.101), and MPA was associated with larger lower- (B: 0.273, 95% CI 0.128-0.419) and whole-body PhA (B: 0.141, 95% CI 0.002-0.280). VPA and PhA were not associated. Future interventions targeting PhA in older adults should consider the differential impact of PA intensity on various body segments of the PhA.
Viral infection induces the production of interleukin (IL)-1β and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 ...activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1β and IL-18 in a cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the cryopyrin inflammasome. Finally, cryopyrin was required for IL-1β production in response to poly(I:C) in vivo. These results identify a mechanism mediated by cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1β and IL-18 production.
Summary
The role of symbiotic bacteria in the development of antigen‐specific immunity remains poorly understood. Previous studies showed that sensing of symbiotic bacteria by nucleotide‐binding ...oligomerization domain‐containing protein 2 (Nod2) regulates antibody responses in response to nasal immunization with antigen and cholera toxin (CT). In this study, we examined the role of the microbiota in the adjuvant activity of CT induced after oral immunization with antigen. Germ‐free (GF) mice showed impaired production of antibody responses and T‐cell‐specific cytokines after oral immunization when compared with that observed in conventionally raised mice. Similar to GF mice, Nod2‐deficient mice showed reduced humoral responses upon oral immunization with antigen and CT. Treatment with CT enhanced the production of interleukin‐1β (IL‐1β), but not tumor necrosis factor‐α or IL‐12p40, induced by stimulation of dendritic cells with muramyl dipeptide, the Nod2 ligand. Mechanistically, the enhanced production of IL‐1β induced by muramyl dipeptide and CT stimulation required Nod2 and was mediated by both increased synthesis of pro‐IL‐1β and caspase‐1 activation. Furthermore, antigen‐specific antibody and cytokine responses induced by CT were impaired in orally immunized IL‐1β‐deficient mice. Collectively, our results indicate that Nod2 stimulation by symbiotic bacteria contributes to optimal CT‐mediated antigen‐specific oral vaccination through the induction of IL‐1β production.
Nod2 stimulation by symbiotic bacteria contributes to optimal cholera toxin (CT)‐mediated antigen‐specific oral vaccination. The induction of interleukin‐1β production by bacterial component (Nod2 ligand), and CT is one of the crucial underlying mechanisms.
The innate immune system comprises several classes of pattern-recognition receptors, including Toll-like receptors (TLRs) and nucleotide binding and oligomerization domain-like receptors (NLRs). TLRs ...recognize microbes on the cell surface and in endosomes, whereas NLRs sense microbial molecules in the cytosol. In this review, we focus on the role of NLRs in host defence against bacterial pathogens. Nod1 and Nod2 sense the cytosolic presence of molecules containing meso-diaminopimelic acid and muramyl dipeptide respectively, and drive the activation of mitogen-activated protein kinase and NF-κB. In contrast, Ipaf, Nalp1b and Cryopyrin/Nalp3 promote the assembly of inflammasomes that are required for the activation of caspase-1. Mutation in several NLR members, including NOD2 and Cryopyrin, is associated with the development of inflammatory disorders. Further understanding of NLRs should provide new insights into the mechanisms of host defence and the pathogenesis of inflammatory diseases.
•Heterotrophic denitrification (HD) process is commonly used in constructed wetlands.•Constructed wetlands are not sufficient for treating hydroponic wastewater.•Hydroponic wastewater contain high ...nitrate and low organic carbon.•Autotrophic denitrification (AD) process is efficient for hydroponic wastewater removal.•The use of combined HD and AD techniques improves nitrate removal in CWs.
To enhance the nitrate removal in constructed wetlands (CWs) for treating hydroponic wastewater discharged from greenhouses, the effectiveness of HF (horizontal flow)-HF hybrid CWs utilizing a combined sulfur-based autotrophic (based on the optimum conditions from batch experiment) and heterotrophic denitrification was evaluated for treating hydroponic wastewater containing high nitrate and low organic carbon concentrations. The optimum ratio of sulfur: limestone:immobilized bead with Thiobacillus denitrificans (T. denitrificans) was found to be 3:1:4; the optimum initial cell density was above 1×106cells; the optimum temperature was 25–35°C; and the optimum sulfur sources were thiosulfate and elemental sulfur to effectively treat hydroponic wastewater utilizing autotrophic denitrification with T. denitrificans in batch experiments. In the HF–HF CWs utilizing the combined autotrophic and heterotrophic denitrification, the average removal efficiencies of nitrate were higher in the order of T2 (71.5%, thiosulfate treatment—combination of heterotrophic and autotrophic denitrification) >T3 (66.6%, element sulfur treatment—combination of heterotrophic and autotrophic denitrification) ≫T1 (43.0%, control—heterotrophic denitrification only). In the HF–HF CWs, the maximum nitrate removal efficiency by the thiosulfate treatment was slightly greater than that by the treatment with elemental sulfur, whereas the sulfate production influence on autotrophic denitrification by elemental sulfur (SO42−: 89.1mgL−1) was lower as compared to thiosulfate (SO42−: 38.3mgL−1). Because the sulfate production is an important factor to meet acceptable drinking water quality discharge standard (Sulfate concentration in the effluent was below 250 in US EPA, and 200mgL−1 in South Korea), elemental sulfur was a more suitable sulfur source in HF–HF hybrid CWs. Overall, a combined process of using E/L/B (element sulfur/limestone/immobilized bead with T. denitrificans) column in HF–HF hybrid CWs would promote autotrophic and heterotrophic denitrification. Therefore, a combined autotrophic and heterotrophic denitrification process in HF–HF CWs would be more suitable than the heterotrophic denitrification alone (conventional technology in CWs) for treating nitrate in hydroponic wastewater since hydroponic wastewater contains little organic carbon.
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