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Background: Kawasaki disease (KD), an acute febrile illness and systemic vasculitis, is the leading cause of acquired heart disease in children in industrialized countries. KD leads to the development of coronary artery aneurysms (CAA) in affected children, which may persist for months and even years after the acute phase of the disease. There is an unmet need to characterize the immune and pathological mechanisms of the long-term complications of KD. Methods: We examined cardiovascular complications in the Lactobacillus casei cell wall extract (LCWE) mouse model of KD-like vasculitis over 4 months. The long-term immune, pathological, and functional changes occurring in cardiovascular lesions were characterized by histological examination, flow cytometric analysis, immunofluorescent staining of cardiovascular tissues, and transthoracic echocardiogram. Results: CAA and abdominal aorta dilations were detected up to 16 weeks following LCWE injection and initiation of acute vasculitis. We observed alterations in the composition of circulating immune cell profiles, such as increased monocyte frequencies in the acute phase of the disease and higher counts of neutrophils. We determined a positive correlation between circulating neutrophil and inflammatory monocyte counts and the severity of cardiovascular lesions early after LCWE injection. LCWE-induced KD-like vasculitis was associated with myocarditis and myocardial dysfunction, characterized by diminished ejection fraction and left ventricular remodeling, which worsened over time. We observed extensive fibrosis within the inflamed cardiac tissue early in the disease and myocardial fibrosis in later stages. Conclusion: Our findings indicate that increased circulating neutrophil counts in the acute phase are a reliable predictor of cardiovascular inflammation severity in LCWE-injected mice. Furthermore, long-term cardiac complications stemming from inflammatory cell infiltrations in the aortic root and coronary arteries, myocardial dysfunction, and myocardial fibrosis persist over long periods and are still detected up to 16 weeks after LCWE injection.
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Pared Celular , Modelos Animales de Enfermedad , Fibrosis , Lacticaseibacillus casei , Síndrome Mucocutáneo Linfonodular , Vasculitis , Animales , Ratones , Pared Celular/inmunología , Vasculitis/inmunología , Vasculitis/etiología , Vasculitis/patología , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/complicaciones , Masculino , Miocarditis/etiología , Miocarditis/patología , Miocarditis/inmunología , Inflamación/inmunologíaRESUMEN
Alterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease (KD), an acute pediatric vasculitis, remains unclear. We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking KD vasculitis. The development of cardiovascular lesions was associated with alterations in the intestinal microbiota composition and, notably, a decreased abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii. Oral supplementation with either of these live or pasteurized individual bacteria, or with short-chain fatty acids (SCFAs) produced by them, attenuated cardiovascular inflammation. Treatment with Amuc_1100, the TLR-2 signaling outer membrane protein from A. muciniphila , also decreased the severity of vascular inflammation. This study reveals an underappreciated gut microbiota-cardiovascular inflammation axis in KD vasculitis pathogenesis and identifies specific intestinal commensals that regulate vasculitis in mice by producing metabolites or via extracellular proteins acting on gut barrier function. IN BRIEF: It remains unclear whether changes in the intestinal microbiota composition are involved in the development of cardiovascular lesions associated with Kawasaki disease (KD), an immune-mediated vasculitis. Jena et al. observe alterations in the intestinal microbiota composition of mice developing vasculitis, characterized by reduced A. muciniphila and F. prausnitzii . Oral supplementation with either of these bacteria, live or pasteurized, or with bacteria-produced short-chain fatty acids (SCFAs) or Amuc_1100, the TLR-2 signaling outer membrane protein of A. muciniphila , was sufficient to alleviate the development of cardiovascular lesions in mice by promoting intestinal barrier function. HIGHLIGHTS: Absence or depletion of the microbiota decreases the severity of vasculitis in a murine model mimicking KD vasculitis. Supplementation of B. wadsworthia and B. fragilis promotes murine KD vasculitis. Decreased abundances of F. prausnitzii and A. muciniphila are associated with the development of cardiovascular lesions in mice. Supplementation with either live or pasteurized A. muciniphila and F. prausnitzii, or the TLR-2 signaling Amuc_1100, reduces the severity of vasculitis by promoting gut barrier function.
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While recent advances in diagnostics and therapeutics offer promising new approaches for Alzheimer's disease (AD) diagnosis and treatment, there is still an unmet need for an effective remedy, suggesting new avenues of research are required. Besides many plausible etiologies for AD pathogenesis, mounting evidence supports a possible role for microbial infections. Various microbes have been identified in the postmortem brain tissues of human AD patients. Among bacterial pathogens in AD, Chlamydia pneumoniae (Cp) has been well characterized in human AD brains and is a leading candidate for an infectious involvement. However, no definitive studies have been performed proving or disproving Cp's role as a causative or accelerating agent in AD pathology and cognitive decline. In this review, we discuss recent updates for the role of Cp in human AD brains as well as experimental models of AD. Furthermore, based on the current literature, we have compiled a list of potential mechanistic pathways which may connect Cp with AD pathology.
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Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.
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[Figure: see text].
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Vasos Sanguíneos/metabolismo , Células Dendríticas/metabolismo , Macrófagos/metabolismo , Síndrome Mucocutáneo Linfonodular/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células del Estroma/metabolismo , Animales , Vasos Sanguíneos/citología , Células Cultivadas , Fibroblastos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Síndrome Mucocutáneo Linfonodular/inmunología , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptores Tipo I de Interleucina-1/metabolismoRESUMEN
Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1ß pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.
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Autofagia , Mitofagia , Síndrome Mucocutáneo Linfonodular/patología , Síndrome Mucocutáneo Linfonodular/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina/sangre , Animales , Autofagia/genética , Proteínas Relacionadas con la Autofagia/genética , Butanos/farmacología , Extractos Celulares , Pared Celular , Vasos Coronarios/patología , ADN Glicosilasas/genética , Modelos Animales de Enfermedad , Hipoglucemiantes/farmacología , Lacticaseibacillus casei , Masculino , Metformina/farmacología , Ratones , Mitofagia/genética , Síndrome Mucocutáneo Linfonodular/inducido químicamente , Síndrome Mucocutáneo Linfonodular/genética , Miocardio/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Compuestos Organofosforados/farmacología , Compuestos de Piridinio/farmacología , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.
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Adenosina Trifosfato/metabolismo , ADN Mitocondrial/biosíntesis , Inflamasomas/efectos de los fármacos , Metformina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neumonía/prevención & control , Animales , COVID-19/metabolismo , COVID-19/prevención & control , Citocinas/genética , Citocinas/metabolismo , ADN Mitocondrial/metabolismo , Humanos , Inflamasomas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolisacáridos/toxicidad , Metformina/uso terapéutico , Ratones , Nucleósido-Fosfato Quinasa/metabolismo , Neumonía/metabolismo , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/prevención & control , SARS-CoV-2/patogenicidadRESUMEN
The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)-deficient macrophages have reduced caspase-1 activity and diminished IL-1ß release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b-dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1ß production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α-CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.
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Cardiolipinas/metabolismo , Interleucina-1alfa/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Autofagia , Cardiolipinas/fisiología , Caspasa 1/metabolismo , Femenino , Células HEK293 , Humanos , Inflamasomas/metabolismo , Interleucina-1alfa/fisiología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/metabolismo , Mitofagia/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Unión Proteica/fisiología , Dominios Proteicos/fisiología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2'-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1-/- mice showed increased influx of Ly6Chi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1-/- mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1-/- mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.
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Daño del ADN/inmunología , Lupus Eritematoso Cutáneo/inmunología , Lupus Eritematoso Sistémico/inmunología , Piel/inmunología , Terpenos/efectos adversos , Animales , ADN Glicosilasas/deficiencia , ADN Glicosilasas/inmunología , Modelos Animales de Enfermedad , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Lupus Eritematoso Cutáneo/inducido químicamente , Lupus Eritematoso Cutáneo/genética , Lupus Eritematoso Cutáneo/patología , Lupus Eritematoso Sistémico/inducido químicamente , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Ratones , Ratones Noqueados , Monocitos/inmunología , Monocitos/patología , Oxidación-Reducción/efectos de los fármacos , Piel/patología , Terpenos/farmacologíaRESUMEN
In the Ldlr -/- mouse model of atherosclerosis, female Nlrp3 -/- bone marrow chimera and Nlrp3 -/- mice developed significantly smaller lesions in the aortic sinus and decreased lipid content in aorta en face, but a similar protection was not observed in males. Ovariectomized female mice lost protection from atherosclerosis in the setting of NLRP3 deficiency, whereas atherosclerosis showed a greater dependency on NLRP3 in castrated males. Thus, castration increased the dependency of atherosclerosis on the NLRP3 inflammasome, suggesting that testosterone may block inflammation in atherogenesis. Conversely, ovariectomy reduced the dependency on NLRP3 inflammasome components for atherogenesis, suggesting that estrogen may promote inflammasome-mediated atherosclerosis.
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In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.
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Antagonistas de Andrógenos/farmacología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Testosterona/metabolismo , Antagonistas de Andrógenos/uso terapéutico , Andrógenos , Animales , Antineoplásicos/farmacología , Médula Ósea/patología , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Femenino , Terapia de Reemplazo de Hormonas/métodos , Pulmón/patología , Masculino , Melanoma/inmunología , Melanoma/patología , Melanoma/terapia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Testosterona/inmunologíaRESUMEN
Targeting inflammasome activation to modulate interleukin (IL)-1ß is a promising treatment strategy against acute respiratory distress syndrome and ventilator-induced lung injury (VILI). Autophagy is a key regulator of inflammasome activation in macrophages. Here, we investigated the role of autophagy in the development of acute lung injury (ALI) induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). Two hours before starting MV, 0.2 mg/kg LPS was administered to mice intratracheally. Mice were then placed on high-volume MV (30 ml/kg with 3 cmH2O positive end-expiratory pressure for 2.5 h without additional oxygen application). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 (Atg16l1fl/flLysMCre) suffered severe hypoxemia (adjusted p < 0.05) and increased lung permeability (p < 0.05, albumin level in bronchoalveolar lavage fluid) with significantly higher IL-1ß release into alveolar space (p < 0.05). Induction of autophagy by fasting-induced starvation led to improved arterial oxygenation (adjusted p < 0.0001) and lung permeability (p < 0.05), as well as significantly suppressed IL-1ß production (p < 0.01). Intratracheal treatment with anti-mouse IL-1ß monoclonal antibody (mAb; 2.5 mg/kg) significantly improved arterial oxygenation (adjusted p < 0.01) as well as lung permeability (p < 0.05). On the other hand, deletion of IL-1α gene or use of anti-mouse IL-1α mAb (2.5 mg/kg) provided no significant protection, suggesting that the LPS and MV-induced ALI is primarily dependent on IL-1ß, but independent of IL-1α. These observations suggest that autophagy has a protective role in controlling inflammasome activation and production of IL-1ß, which plays a critical role in developing hypoxemia and increased lung permeability in LPS plus MV-induced acute lung injury.
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Autofagia/fisiología , Hipoxia/prevención & control , Inflamasomas/fisiología , Interleucina-1beta/fisiología , Lipopolisacáridos/toxicidad , Pulmón/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/etiología , Animales , Regulación hacia Abajo , Interleucina-18/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Permeabilidad , Serina-Treonina Quinasas TOR/fisiología , Trehalosa/uso terapéutico , Lesión Pulmonar Inducida por Ventilación Mecánica/inmunologíaRESUMEN
Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1ß (IL-1ß) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1ß signaling, we demonstrate that IL-1ß lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1ß pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.
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Enfermedades Cardiovasculares/inmunología , Inmunoglobulina A/inmunología , Inflamación/inmunología , Intestinos/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Interleucina-1beta/inmunología , Ratones , Ratones Endogámicos C57BL , Síndrome Mucocutáneo Linfonodular/inmunología , Permeabilidad , Transducción de Señal/inmunología , Vasculitis/inmunologíaRESUMEN
Autophagy can either antagonize or promote intracellular bacterial growth, depending on the pathogen. Here, we investigated the role of autophagy during a pulmonary infection with the obligate intracellular pathogen, Chlamydia pneumoniae (CP). In mouse embryonic fibroblasts (MEFs) or macrophages, deficiency of autophagy pathway components led to enhanced CP replication, suggesting that autophagy exerts a bactericidal role. However, in vivo, mice with myeloid-specific deletion of the autophagic protein ATG16L1 suffered increased mortality during CP infection, neutrophilia, and increased inflammasome activation despite no change in bacterial burden. Induction of autophagy led to reduced CP replication in vitro, but impaired survival in CP-infected mice, associated with an initial reduction in IL-1ß production, followed by enhanced neutrophil recruitment, defective CP clearance, and later inflammasome activation and IL-1ß production, which drove the resulting mortality. Taken together, our data suggest that a delicate interplay exists between autophagy and inflammasome activation in determining the outcome of CP infection, perturbation of which can result in inflammatory pathology or unrestricted bacterial growth.
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Autofagia , Infecciones por Chlamydophila/metabolismo , Infecciones por Chlamydophila/microbiología , Chlamydophila pneumoniae/fisiología , Inflamasomas/metabolismo , Animales , Biomarcadores , Fibroblastos/metabolismo , Fibroblastos/microbiología , Citometría de Flujo , Técnicas de Inactivación de Genes , Macrófagos/metabolismo , Macrófagos/microbiología , RatonesRESUMEN
Kawasaki disease (KD), the leading cause of acquired cardiac disease among children, is often associated with myocarditis that may lead to long-term myocardial dysfunction and fibrosis. Although those myocardial changes develop during the acute phase, they may persist for decades and closely correlate with long-term myocardial sequelae. Using the Lactobacillus casei cell wall extract-induced (LCWE-induced) KD vasculitis murine model, we investigated long-term cardiovascular sequelae, such as myocardial dysfunction, fibrosis, and coronary microvascular lesions following adrenergic stimuli after established KD vasculitis. We found that adrenergic stimulation with isoproterenol following LCWE-induced KD vasculitis in mice was associated with increased risk of cardiac hypertrophy and myocardial fibrosis, diminished ejection fraction, and increased serum levels of brain natriuretic peptide. Myocardial fibrosis resulting from pharmacologic-induced exercise after KD development was IL-1 signaling dependent and was associated with a significant reduction in myocardial capillary CD31 expression, indicative of a rarefied myocardial capillary bed. These observations suggest that adrenergic stimulation after KD vasculitis may lead to cardiac hypertrophy and bridging fibrosis in the myocardium in the LCWE-induced KD vasculitis mouse model and that this process involves IL-1 signaling and diminished microvascular circulation in the myocardium.
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Endotracheal tube (ETT) management is an essential technique in handling mice with mechanical ventilators. Malposition into bronchi causes not only lethal complications for them but also less efficient mechanical ventilation. However, in general, it is difficult to know whether the ETT is placed with appropriate depth into the trachea of mice. We measured the distance from incisors to the bifurcation of trachea of multiple mice, and created a new estimation formula to obtain the suitable ETT length for mice with a body weight range from 17 g to 25 g: length (mm) = 0.5 × bodyweight (g) + 7. However, millimeter step adjustments are impracticable. Thus, slightly shorter than 2 cm (18-20 mm) may be the universal ETT length for mice with bodyweight > 17 g. Furthermore, their foot size may be a good alternative to predict the individual optimal ETT length for mice.
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Intubación Intratraqueal/métodos , Ratones/cirugía , Tráquea/cirugía , Animales , Femenino , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
Receptor interacting protein 2 (RIP2) plays a role in sensing intracellular pathogens, but its function in T cells is unclear. We show that RIP2 deficiency in CD4+ T cells resulted in chronic and severe interleukin-17A-mediated inflammation during Chlamydia pneumoniae lung infection, increased T helper 17 (Th17) cell formation in lungs of infected mice, accelerated atherosclerosis, and more severe experimental autoimmune encephalomyelitis. While RIP2 deficiency resulted in reduced conventional Th17 cell differentiation, it led to significantly enhanced differentiation of pathogenic (p)Th17 cells, which was dependent on RORα transcription factor and interleukin-1 but independent of nucleotide oligomerization domain (NOD) 1 and 2. Overexpression of RIP2 resulted in suppression of pTh17 cell differentiation, an effect mediated by its CARD domain, and phenocopied by a cell-permeable RIP2 CARD peptide. Our data suggest that RIP2 has a T cell-intrinsic role in determining the balance between homeostatic and pathogenic Th17 cell responses.
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Diferenciación Celular/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Células Th17/citología , Células Th17/metabolismo , Animales , Aterosclerosis , Biomarcadores , Dominio de Reclutamiento y Activación de Caspasas , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/mortalidad , Expresión Génica , Inmunofenotipificación , Inflamación/genética , Inflamación/metabolismo , Interleucina-17/biosíntesis , Interleucina-1beta , Ratones , Ratones Noqueados , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor , Proteína Serina-Treonina Quinasas de Interacción con Receptores/química , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
The gastrointestinal microbiota influences immune function throughout the body. The gut-lung axis refers to the concept that alterations of gut commensal microorganisms can have a distant effect on immune function in the lung. Overgrowth of intestinal Candida albicans has been previously observed to exacerbate allergic airways disease in mice, but whether subtler changes in intestinal fungal microbiota can affect allergic airways disease is less clear. In this study we have investigated the effects of the population expansion of commensal fungus Wallemia mellicola without overgrowth of the total fungal community. Wallemia spp. are commonly found as a minor component of the commensal gastrointestinal mycobiota in both humans and mice. Mice with an unaltered gut microbiota community resist population expansion when gavaged with W. mellicola; however, transient antibiotic depletion of gut microbiota creates a window of opportunity for expansion of W. mellicola following delivery of live spores to the gastrointestinal tract. This phenomenon is not universal as other commensal fungi (Aspergillus amstelodami, Epicoccum nigrum) do not expand when delivered to mice with antibiotic-depleted microbiota. Mice with Wallemia-expanded gut mycobiota experienced altered pulmonary immune responses to inhaled aeroallergens. Specifically, after induction of allergic airways disease with intratracheal house dust mite (HDM) antigen, mice demonstrated enhanced eosinophilic airway infiltration, airway hyperresponsiveness (AHR) to methacholine challenge, goblet cell hyperplasia, elevated bronchoalveolar lavage IL-5, and enhanced serum HDM IgG1. This phenomenon occurred with no detectable Wallemia in the lung. Targeted amplicon sequencing analysis of the gastrointestinal mycobiota revealed that expansion of W. mellicola in the gut was associated with additional alterations of bacterial and fungal commensal communities. We therefore colonized fungus-free Altered Schaedler Flora (ASF) mice with W. mellicola. ASF mice colonized with W. mellicola experienced enhanced severity of allergic airways disease compared to fungus-free control ASF mice without changes in bacterial community composition.
Asunto(s)
Basidiomycota/inmunología , Basidiomycota/patogenicidad , Microbioma Gastrointestinal/inmunología , Micobioma/inmunología , Hipersensibilidad Respiratoria/etiología , Alérgenos/administración & dosificación , Animales , Antibacterianos/efectos adversos , Antígenos Dermatofagoides/administración & dosificación , Basidiomycota/crecimiento & desarrollo , Modelos Animales de Enfermedad , Microbiología Ambiental , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Vida Libre de Gérmenes/inmunología , Humanos , Ratones , Ratones Endogámicos C57BL , Micobioma/genética , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/microbiología , Simbiosis/inmunologíaRESUMEN
BACKGROUND: Recruited myeloid cells are known to promote cancer initiation, malignant progression, metastasis, and resistance to therapy in the tumor niche. We tested the hypothesis that circulating blood monocytes from advanced prostate cancer (PCa) patients exhibit a protumor phenotype and directly influence the tumor microenvironment in response to tumor-derived signals. METHODS: Blood monocytes from advanced and stable PCa patients were cultured, and the conditioned media (CM) were collected and analyzed using standard invasion and wound closure assays to measure effects on invasion and motility of PCa tumor cells. We then identified the proteome profile of these monocytes using proteome array and ELISA. RESULTS: Conditioned media from circulating monocytes in patients with metastatic prostate cancer (PCa-M) increased invasion of epithelial PCa cells in vitro. Proteome Profiler Analysis revealed that monocyte-derived CM from metastatic castration-resistant (mCRPC) patients presented high levels of chitinase-3-like 1 (CHI3L1, YKL-40) when compared to patients with stable disease (PCa-N) and healthy control individuals (HC). The only described receptor for CHI3L1, interleukin-13 receptor α2 (IL-13Rα2), was significantly up-regulated in the human metastatic PCa cell line, ARCaPM . Accordingly, we observed that the activation of IL-13Rα2 from PCa-M CM increased the invasiveness of ARCaPM cells while siRNA directed against this receptor significantly reduced invasiveness of these cells in the presence of CM from PCa-M patients. CONCLUSIONS: Thus, we show that circulating monocytes from metastatic PCa patients exert a tumor-promoting role via the secretion of CHI3L1, and CHI3L1 demands further exploration as a possible therapeutic target in advanced PCa.