RESUMO
Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S. aureus infection led to S. aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S. aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S. aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S. aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S. aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.
Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Animais , Feminino , Bovinos , Staphylococcus aureus/fisiologia , Rifampina/farmacologia , Rifampina/uso terapêutico , Imunidade Treinada , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , BactériasRESUMO
Trained immunity is mechanistically defined as the metabolically and epigenetically mediated long-term functional adaptation of the innate immune system, characterized by a heightened response to a secondary stimulation. Given appropriate activation, trained immunity represents an attractive anti-infective therapeutic target. Nevertheless, excessive immune response and subsequent inflammatory cascades may contribute to pathological tissue damage, indicating that the negative impacts of trained immunity appear to be significant. In this study, we show that innate immune responses such as the production of extracellular traps, pro-inflammatory cytokines, and autophagy-related proteins were markedly augmented in trained BMDMs. Furthermore, heat-killed C. albicans priming promotes the activation of the AIM2 inflammasome, and AIM2-/- mice exhibit impaired memory response induced by heat-killed C. albicans. Therefore, we establish that the AIM2 inflammasome is involved in trained immunity and emerges as a promising therapeutic target for potentially deleterious effects. Dihydroartemisinin can inhibit the memory response induced by heat-killed C. albicans through modulation of mTOR signaling and the AIM2 inflammasome. The findings suggest that dihydroartemisinin can reduce the induction of trained immunity by heat-killed C. albicans in C57BL/6 mice. Dihydroartemisinin is one such therapeutic intervention that has the potential to treat of diseases characterized by excessive trained immunity.
Assuntos
Artemisininas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Imunidade Treinada , Animais , Camundongos , Artemisininas/farmacologia , Candida albicans/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Imunidade Treinada/efeitos dos fármacosRESUMO
With the widespread use of antibiotics, the incidence of antibiotic resistance in microorganisms has increased. Monochamus alternatus is a trunk borer of pine trees. This study aimed to investigate the in vitro antimicrobial and biological characteristics of Enterococcus casseliflavus TN-47 (PP411196), isolated from the gastrointestinal tract of M. alternatus in Jilin Province, PR China. Among 13 isolates obtained from the insects, five were preliminarily screened for antimicrobial activity. E. casseliflavus TN-47, which exhibited the strongest antimicrobial activity, was identified. E. casseliflavus TN-47 possessed antimicrobial activity against Staphylococcus aureus USA300 and Salmonella enterica serovar Pullorum ATCC 19945. Furthermore, E. casseliflavus TN-47 was sensitive to tetracyclines, penicillins (ampicillin, carbenicillin, and piperacillin), quinolones and nitrofuran antibiotics, and resistant to certain beta-lactam antibiotics (oxacillin, cefradine and cephalexin), macrolide antibiotics, sulfonamides and aminoglycosides. E. casseliflavus TN-47 could tolerate low pH and pepsin-rich conditions in the stomach and grow in the presence of bile acids. E. casseliflavus TN-47 retained its strong auto-aggregating ability and hydrophobicity. This strain did not exhibit any haemolytic activity. These results indicate that E. casseliflavus TN-47 has potential as a probiotic. This study provides a theoretical foundation for the future applications of E. casseliflavus TN-47 and its secondary metabolites in animal nutrition and feed.
Assuntos
Besouros , Enterococcus , Ácidos Graxos , Animais , Filogenia , Análise de Sequência de DNA , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , Técnicas de Tipagem Bacteriana , Composição de Bases , Ácidos Graxos/química , Antibacterianos/farmacologia , OxacilinaRESUMO
Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STINGdeficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.
Assuntos
Infecções por Clostridium , Animais , Camundongos , Infecções por Clostridium/veterinária , Clostridium perfringens , Interleucina-6 , Lipopolissacarídeos , Serina-Treonina Quinases TOR , Imunidade Treinada , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Interferon-inducible protein 204 (IFI204) is an intracellular DNA receptor that can recognize DNA viruses and intracellular bacteria. Extracellular traps (ETs) have been recognized as an indispensable antimicrobial barrier that play an indispensable role in bacterial, fungal, parasitic, and viral infections. However, how ETs form and the mechanisms by which IFI204 function in Staphylococcus aureus pneumonia are still unclear. Moreover, by in vitro experiments, we proved that IFI204 deficiency decreases the formation of ETs induced by Staphylococcus aureus in a NOX-independent manner. More importantly, Deoxyribonuclease I (DNase I) treatment significantly inhibited the formation of ETs. IFI204 contributed to ETs formation by promoting citrullination of histone H3 and the expression of PAD4 (peptidylarginine deiminase 4). Altogether, these findings highlight the potential importance of IFI204 for host defense against S. aureus USA300-TCH1516 infection.
Assuntos
Armadilhas Extracelulares , Pneumonia Estafilocócica , Armadilhas Extracelulares/genética , Armadilhas Extracelulares/metabolismo , Interferons/metabolismo , Neutrófilos/metabolismo , Pneumonia Estafilocócica/genética , Pneumonia Estafilocócica/metabolismo , Staphylococcus aureus , Camundongos , AnimaisRESUMO
The extensive use of plastic products in food packaging and daily life makes them inevitably enter the treatment process of food waste (FW). Plasticizer as a new pollutant is threatening the dark fermentation of FW. Our study showed that bisphenol A (BPA) at > 250 mg/L had a significant inhibition on hydrogen production from FW by thermophilic dark fermentation. The endogenous ATP content and lactate dehydrogenase (LDH) release showed that high level of BPA not only inhibited the growth of hydrogen-producing consortium, but also led to cell death. In addition, BPA mainly affects the hydrogen-producing consortium by reducing cell membrane fluidity, damaging cell membrane integrity and reducing cell membrane potential, resulting in cell death. This study provides some new insights into the mechanism of the effect of BPA on hydrogen production from FW by thermophilic dark fermentation, and lays the foundation on the utilization of FW.
RESUMO
Pure cultures of chicken intestinal microbial species may still be crucial and imperative to expound on the function of gut microbiota, and also contribute to the development of potential probiotics and novel bioactive metabolites from gut microbiota. In this study, we isolated and identified 507 chicken intestinal bacterial isolates, including 89 previously uncultured isolates. Among these, a total of 63 Lactobacillus strains, belonging to L. vaginalis, L. crispatus, L. gallinarum, L. reuteri, L. salivarius, and L. saerimneri, exhibited antibacterial activity against S. Pullorum. Acid tolerance tests showed Limosilactobacillus reuteri strain YPG14 (L. reuteri strain YPG14) has a particularly strong tolerance to acid. We further characterized other probiotic properties of L. reuteri strain YPG14. In simulated intestinal fluid, the growth of L. reuteri strain YPG14 remained stable after incubation for 4 h. The auto-aggregation test showed the auto-aggregation percentage of L. reuteri strain YPG14 was recorded as 15.0 ± 0.38%, 48.3 ± 2.51%, and 75.1 ± 4.44% at 3, 12, and 24 h, respectively. In addition, the mucin binding assay showed L. reuteri strain YPG14 exhibited 12.07 ± 0.02% adhesion to mucin. Antibiotic sensitivity testing showed that L. reuteri strain YPG14 was sensitive to the majority of the tested antibiotics. The anti-Salmonella Pullorum (S. Pullorum) infection effect in vivo revealed that the consumption of L. reuteri strain YPG14 could significantly improve body weight loss and survival rate of chicks infected by S. Pullorum; reduce the loads of S. Pullorum in the jejunum, liver, spleen, and feces; and alleviate the jejunum villi morphological structure damage, crypt loss, and inflammatory cell infiltration caused by S. Pullorum. Overall, this study may help us to understand the diversity of chicken intestinal microflora and provide some insights for potential probiotic development from gut microbiota and may find application in the poultry industry.
Assuntos
Microbioma Gastrointestinal , Limosilactobacillus reuteri , Probióticos , Animais , Galinhas , Intestinos/microbiologia , Antibacterianos/farmacologia , Probióticos/farmacologia , MucinasRESUMO
BACKGROUND: Drug-resistant bacteria have posed a great threat to animal breeding and human health. It is obviously urgent to develop new antibiotics that can effectively combat drug-resistant bacteria. The commensal flora inhabited in the intestines become potential candidates owing to the production of a wide range of antimicrobial substances. In addition, host genomes do not encode most of the enzymes needed to degrade dietary structural polysaccharides. The decomposition of these polysaccharides mainly depends on gut commensal-derived CAZymes. RESULTS: We report a novel species isolated from the chicken intestine, designated as Paenibacillus jilinensis sp. nov. and with YPG26T (= CCTCC M2020899T) as the type strain. The complete genome of P. jilinensis YPG26T is made up of a single circular chromosome measuring 3.97 Mb in length and containing 49.34% (mol%) G + C. It carries 33 rRNA genes, 89 tRNA genes, and 3871 protein-coding genes, among which abundant carbohydrate-degrading enzymes (CAZymes) are encoded. Moreover, this strain has the capability to antagonize multiple pathogens in vitro. We identified putative 6 BGCs encoding bacteriocin, NRPs, PKs, terpenes, and protcusin by genome mining. In addition, antibiotic susceptibility testing showed sensitivity to all antibiotics tested. CONCLUSIONS: This study highlights the varieties of CAZymes genes and BGCs in the genome of Paenibacillus jilinensis. These findings confirm the beneficial function of the gut microbiota and also provide a promising candidate for the development of new carbohydrate degrading enzymes and antibacterial agents.
Assuntos
Anti-Infecciosos , Paenibacillus , Antibacterianos , Técnicas de Tipagem Bacteriana , DNA Bacteriano/genética , Ácidos Graxos/análise , Família Multigênica , Paenibacillus/genética , Filogenia , Polissacarídeos , RNA Ribossômico 16S/genética , Análise de Sequência de DNARESUMO
Obesity is one of the prevalent chronic diseases in human and companion animals usually associated with several metabolic disorders. The gut commensal bacterium Akkermansia muciniphila (A. muciniphila) is known for its therapeutic effects on metabolic disorders and inflammations. Here, we isolated the A. muciniphila AKK2 strain from the feces of interferon-inducible protein 204-/- (IFI204-/-) mice and further evaluated its anti-obesity effects on high-fat diet (HFD)-fed C57BL/6J mice and beagles. The results showed that it effectively controlled weight gain. Microbiome analysis using 16S rRNA gene sequencing revealed that HFD alters gut microbiota composition and A. muciniphila AKK2 increases the Firmicutes/Bacteroidetes (F/B) ratio in beagles. Furthermore, we prepared microcapsules containing A. muciniphila AKK2, and tolerance tests showed the encapsulation maintained high viability and stability in an aerobic environment and simulated the secretion of gastrointestinal fluids. Overall, this study widens the spectrum of A. muciniphila applications to prevent obesity.
Assuntos
Dieta Hiperlipídica , Doenças Metabólicas , Akkermansia , Animais , Cápsulas , Cães , Humanos , Interferons , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/microbiologia , RNA Ribossômico 16S/genética , Verrucomicrobia/genéticaRESUMO
Gasdermin D (GSDMD), a member of the gasdermin protein family, is a caspase substrate, and its cleavage is required for pyroptosis and IL-1ß secretion. To date, the role and regulatory mechanism of GSDMD during cutaneous microbial infection remain unclear. Here, we showed that GSDMD protected against Staphylococcus aureus skin infection by suppressing Cxcl1-Cxcr2 signalling. GSDMD deficiency resulted in larger abscesses, more bacterial colonization, exacerbated skin damage, and increased inflammatory cell infiltration. Although GSDMD deficiency resulted in defective IL-1ß production, the critical role of IL-1ß was counteracted by the fact that Caspase-1/11 deficiency also resulted in less IL-1ß production but did not aggravate disease severity during S. aureus skin infection. Interestingly, GSDMD-deficient mice had increased Cxcl1 secretion accompanied by increased recruitment of neutrophils, whereas Caspase-1/11-deficient mice presented similar levels of Cxcl1 and neutrophils as wild-type mice. Moreover, the absence of GSDMD promoted Cxcl1 secretion in bone marrow-derived macrophages induced by live, dead, or different strains of S. aureus. Corresponding to higher transcription and secretion of Cxcl1, enhanced NF-κB activation was shown in vitro and in vivo in the absence of GSDMD. Importantly, inhibiting the Cxcl1-Cxcr2 axis with a Cxcr2 inhibitor or anti-Cxcl1 blocking antibody rescued host defence defects in the GSDMD-deficient mice. Hence, these results revealed an important role of GSDMD in suppressing the Cxcl1-Cxcr2 axis to facilitate pathogen control and prevent tissue damage during cutaneous S. aureus infection.
Assuntos
Quimiocina CXCL1/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Ligação a Fosfato/genética , Receptores de Interleucina-8B/genética , Dermatopatias/veterinária , Infecções Estafilocócicas/veterinária , Staphylococcus aureus/fisiologia , Animais , Quimiocina CXCL1/imunologia , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Ligação a Fosfato/imunologia , Receptores de Interleucina-8B/imunologia , Dermatopatias/genética , Dermatopatias/imunologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologiaRESUMO
The gut microbiota and microRNAs play important roles in the defense against infection. However, the role of miR-146a in L. monocytogenes infection and gut microbiota remains unclear. We tried to determine whether miR-146a controlled L. monocytogenes infection by regulating the gut microbiota. Wild-type and miR-146a-deficient mice or macrophages were used to characterize the impact of miR-146a on animal survival, cell death, bacterial clearance, and gut microbiota following L. monocytogenes challenge. We found that L. monocytogenes infection induced miR-146a expression both in vitro and in vivo. When compared to wild-type mice, miR-146a-deficient mice were more resistant to L. monocytogenes infection. MiR-146a deficiency in macrophages resulted in reduced invasion and intracellular survival of L. monocytogenes. High-throughput sequencing of 16S rRNA revealed that the gut microbiota composition differed between miR-146a-deficient and wild-type mice. Relative to wild-type mice, miR-146a-deficient mice had decreased levels of the Proteobacteria phylum, Prevotellaceae family, and Parasutterella genus, and significantly increased short-chain fatty acid producing bacteria, including the genera Alistipes, Blautia, Coprococcus_1, and Ruminococcus_1. Wild-type mice co-housed with miR-146a-deficient mice had increased resistance to L. monocytogenes, indicating that miR-146a deficiency guides the gut microbiota to alleviate infection. Together, these results suggest that miR-146a deficiency protects against L. monocytogenes infection by regulating the gut microbiota.
Assuntos
Bactérias/classificação , Resistência à Doença , Listeria monocytogenes/patogenicidade , Listeriose/prevenção & controle , MicroRNAs/genética , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Microbioma Gastrointestinal , Sequenciamento de Nucleotídeos em Larga Escala , Listeriose/genética , Camundongos , Mutação , Filogenia , Células RAW 264.7 , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Análise de Sequência de DNARESUMO
Inflammasomes are multiprotein complexes that control the production of IL-1ß and IL-18. NLRP3 inflammasome, the most characterized inflammasome, plays prominent roles in defense against infection, however aberrant activation is deleterious and leads to diseases. Therefore, its tight control offers therapeutic promise. Liver X receptors (LXRs) have significant anti-inflammatory properties. Whether LXRs regulate inflammasome remains unresolved. We thus tested the hypothesis that LXR's anti-inflammatory properties may result from its ability to suppress inflammasome activation. In this study, LXRs agonists inhibited the induction of IL-1ß production, caspase-1 cleavage and ASC oligomerization by NLRP3 inflammasome. The agonists also inhibited inflammasome-associated mtROS production. Importantly, the agonists inhibited the priming of inflammasome activation. In vivo data also showed that LXRs agonist prevented NLRP3-dependent peritonitis. In conclusion, LXRs agonists are identified to potently suppress NLRP3 inflammasome and the regulation of LXRs signaling is a potential therapeutic for inflammasome-driven diseases.
Assuntos
Inflamassomos/imunologia , Receptores X do Fígado/agonistas , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Peritonite/imunologia , Transdução de Sinais/imunologia , Animais , Caspase 3/imunologia , Linhagem Celular , Interleucina-1beta/imunologia , Receptores X do Fígado/imunologia , Camundongos , Peritonite/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: There does not exist a comprehensive parameter for guiding selection of short or long segment fusion for degenerative lumbar scoliosis (DLS). The aim of our study was to investigate the applications of the width-to-length ratio in guiding selection of the surgical approaches for DLS. METHODS: A retrospective analysis was performed of 142 patients with DLS who underwent operative treatments from July 2000 to January 2012. The scoliosis width-to-length ratios were measured and used as a grouping criterion of surgical approaches. The Oswestry disability index (ODI) was used to evaluate the clinical outcomes. Radiological parameters such as Cobb's angle of main curve, Cobb's angle of compensatory curve were all measured. RESULTS: For patients with width-to-length ratio less than 0.36, the short segment group had better short-term postoperative outcomes with regard to Cobb's angle of main curve, Cobb's angle of compensatory curve and ODI scores compared to the long segment group. However, for patients with width-to-length ratio greater than 0.36, the postoperative outcomes for the long segment group were better compared to the short segment group. CONCLUSIONS: The scoliosis width-to-length ratio can provide a comprehensive preoperative assessment of the severity of the DLS and guiding selection of a therapeutic treatment regimen. Further studies with a larger number of samples and longer term of follow up are warranted.
Assuntos
Tomada de Decisão Clínica/métodos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Escoliose/diagnóstico por imagem , Escoliose/cirurgia , Idoso , Descompressão Cirúrgica/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Estudos Retrospectivos , Fusão Vertebral/métodos , Resultado do TratamentoRESUMO
The mechanisms underlying the immune defense by trophoblasts against pathogens remain ill defined. We demonstrated that placental cell death was increased upon in vivo exposure to Listeria monocytogenes. The death of infected cells is an important host innate defense mechanism. Meanwhile, double-stranded DNA (dsDNA) derived from intracellular bacteria or dsDNA viruses is emerging as a potent pathogen-associated molecular pattern recognized by host cells. We sought to characterize trophoblast death in response to cytosolic dsDNA challenge. Our results showed that dsDNA induced caspase-dependent and -independent cell death in human trophoblasts. However, necroptosis, a cell death pathway independent of caspase, could not be induced by dsDNA treatment, even in the presence of exogenously expressed RIPK3. L. monocytogenes-derived genomic DNA triggered a similar cell death pattern. Moreover, the cell death in response to dsDNA was IFI16 dependent. These data suggest that cytosolic dsDNA induces nonnecroptotic cell death in trophoblasts via IFI16, and this could contribute to placental barrier against infection.
Assuntos
Morte Celular/efeitos dos fármacos , DNA/farmacologia , Listeria monocytogenes/efeitos dos fármacos , Proteínas Nucleares/fisiologia , Fosfoproteínas/fisiologia , Trofoblastos/microbiologia , Animais , Caspases/metabolismo , Linhagem Celular , DNA Bacteriano/farmacologia , Feminino , Humanos , Listeria monocytogenes/fisiologia , Listeriose/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Gravidez , Trofoblastos/efeitos dos fármacosRESUMO
The rise of antibiotic resistance poses a significant public health crisis, particularly due to limited antimicrobial options for the treatment of infections with Gram-negative pathogens. Here, an antimicrobial peptide (AMP) SR25 is characterized, which effectively kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism without detectable resistance. Meanwhile, an SR25-functionalized hydrogel is developed for the efficient treatment of infected diabetic wounds. SR25 is obtained through genome mining from an uncultured bovine enteric actinomycete named Nonomuraea Jilinensis sp. nov. Investigations reveal that SR25 has two independent cellular targets, disrupting bacterial membrane integrity and restraining the activity of succinate:quinone oxidoreductase (SQR). In a diabetic mice wound infection model, the SR25-incorporated hydrogel exhibits high efficacy against mixed infections of Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA), accelerating wound healing. Overall, these findings demonstrate the therapeutic potential of SR25 and highlight the value of mining drugs with multiple mechanisms from uncultured animal commensals for combating challenging bacterial pathogens.
Assuntos
Diabetes Mellitus Experimental , Modelos Animais de Doenças , Cicatrização , Animais , Camundongos , Cicatrização/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptídeos Antimicrobianos/farmacologia , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade MicrobianaRESUMO
Mast cells play a central role in allergic inflammation and are activated through cross-linking of FcεRI receptor-bound IgE, initiating a signaling cascade resulting in production of biologically potent mediators. Signaling pathways in the regulation of specific mediators remain incompletely defined. In this study, we examined the role of MAPK kinase 3 (MKK3) in IgE-dependent mast cell activation. In an in vivo model of passive cutaneous anaphylaxis, MKK3-deficient mice showed a deficit in late-phase IgE-dependent inflammation. To characterize the mechanism of this deficiency, we cultured bone marrow-derived mast cells (BMMCs) from wild-type and MKK3-deficient mice. We found that FcεRI-mediated mast cell activation induced rapid MKK3 phosphorylation by 5 min, diminishing slowly after 6 h. In MKK3-deficient BMMCs, phosphorylation of p38 was reduced at early and later time points. Among 40 cytokines tested using a protein array, IL-4 was the only cytokine specifically downregulated in MKK3-deficient BMMCs. Reduced IL-4 expression was seen in the local skin of MKK3-deficient mice following passive cutaneous allergic reaction. Furthermore, early growth response-1 (Egr1) bound to the promoter of IL-4 in FcεRI-activated mast cells, and Egr1 transcription factor activity was diminished in MKK3-deficient BMMCs. Finally, mast cell-deficient mice reconstituted with MKK3-deficient BMMCs displayed a significantly impaired late-phase allergic inflammatory response. Thus, mast cell MKK3 signaling contributes to IgE-dependent allergic inflammation and is a specific regulator of FcεRI-induced IL-4 production.
Assuntos
Interleucina-4/biossíntese , MAP Quinase Quinase 3/imunologia , Mastócitos/imunologia , Receptores de IgE/imunologia , Transdução de Sinais/imunologia , Animais , Western Blotting , Degranulação Celular/imunologia , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Imuno-Histoquímica , Interleucina-4/imunologia , MAP Quinase Quinase 3/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Anafilaxia Cutânea Passiva/imunologia , Análise Serial de ProteínasRESUMO
BACKGROUND: There is still controversy surrounding routine ilioinguinal neurectomy in open tension-free inguinal hernia repair. METHOD: PubMed, Cochrane Library and EMBASE databases were searched for randomized controlled trials of ilioinguinal neurectomy in open tension-free inguinal hernia repair. Revman 5.3 software was used for meta-analysis. RESULT: Meta-analysis revealed that the incidence of severe pain on the first postoperative day was lower in the ilioinguinal neurectomy group (ING) than in the ilioinguinal nerve preservation group (INPG) [P < 0.0001]. The incidence of no pain in the first month postoperatively [P = 0.0004], the incidence of no pain in the sixth months postoperatively [P < 0.00001], and the numbness incidence in the first month postoperatively [P = 0.001] in the ING was higher than that in the INPG. There was no significant difference in the incidence of severe pain in the first month postoperatively [P = 0.20], the numbness incidence in the sixth postoperative month [P = 0.05], the hypoesthesia incidence in the first [P = 0.15] and sixth [P = 0.85] postoperative months between the two groups. CONCLUSION: Ilioinguinal neurectomy in open tension-free inguinal hernia repair can better prevent postoperative pain.
Assuntos
Hérnia Inguinal , Humanos , Hérnia Inguinal/cirurgia , Hérnia Inguinal/complicações , Hipestesia/complicações , Hipestesia/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/cirurgia , Denervação/efeitos adversos , Telas Cirúrgicas/efeitos adversos , Herniorrafia/efeitos adversosRESUMO
[This corrects the article DOI: 10.1016/j.isci.2022.105121.].
RESUMO
The presence of eosinophils in the lung is often regarded as a defining feature of asthma. On allergen stimulation, numbers of eosinophils and their progenitors are increased in both the bone marrow and lungs. Eosinophil progenitors provide an ongoing supply of mature eosinophils. Here, we report that deficiency in the regulator of calcineurin 1 gene (Rcan1) leads to a near-complete absence of eosinophilia in ovalbumin-induced allergic asthma in mice. In the absence of Rcan1, bone marrow cells produce significantly fewer eosinophils in vivo and in vitro on interleukin-5 stimulation. Importantly, eosinophil progenitor populations are significantly reduced in both naïve and ovalbumin-challenged Rcan1(-/-) mice. Bone marrow cells from Rcan1(-/-) mice are capable of developing into fully mature eosinophils, suggesting that Rcan1 is required for eosinophil progenitor production but may not be necessary for eosinophil maturation. Thus, Rcan1 represents a novel contributor in the development of eosinophilia in allergic asthma through regulation of eosinophil progenitor production.