RESUMEN
The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.
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Isquemia Encefálica/inmunología , Accidente Cerebrovascular Isquémico/inmunología , Microglía/inmunología , Osteopontina/inmunología , Recuperación de la Función/inmunología , Linfocitos T Reguladores/inmunología , Sustancia Blanca/inmunología , Animales , Modelos Animales de Enfermedad , Interleucina-2/inmunología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Microglia play essential roles in neuroinflammatory responses after traumatic brain injury (TBI). Our previous studies showed that phenotypes of microglia, as well as infiltrating macrophages, altered at different stages after CNS injury, which was correlated to functional outcomes. IL-13 is an anti-inflammatory cytokine that has been reported to protect against demyelination and spinal cord injury through immunomodulation. The effects of IL-13 in microglia/macrophage-mediated immune responses after TBI remain unknown. In this study, we showed that intranasal administration of IL-13 in male C57BL/6J mice accelerated functional recovery in the controlled cortical impact model of TBI. IL-13 treatment increased the time to fall off in the Rotarod test, reduced the number of foot faults in the foot fault test, and improved the score in the wire hang test up to 28 d after TBI. Consistent with functional improvement, IL-13 reduced neuronal tissue loss and preserved white matter integrity 6 d after TBI. Furthermore, IL-13 ameliorated the elevation of proinflammatory factors and reduced the number of proinflammatory microglia/macrophages 6 d after TBI. Additionally, IL-13 enhanced microglia/macrophage phagocytosis of damaged neurons in the peri-lesion areas. In vitro studies confirmed that IL-13 treatment inhibited the production of proinflammatory cytokines in rat primary microglia in response to LPS or dead neuron stimulation and increased the ability of microglia to engulf fluorophore-labeled latex beads or dead neurons. Collectively, we demonstrated that IL-13 treatment improved neurologic outcomes after TBI through adjusting microglia/macrophage phenotypes and inhibiting inflammatory responses. IL-13 may represent a potential immunotherapy to promote long-term recovery from TBI.
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Antiinflamatorios/administración & dosificación , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Encefalitis/tratamiento farmacológico , Interleucina-13/administración & dosificación , Recuperación de la Función/efectos de los fármacos , Administración Intranasal , Animales , Técnicas de Observación Conductual , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/inmunología , Lesiones Traumáticas del Encéfalo/fisiopatología , Células Cultivadas , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalitis/inmunología , Encefalitis/fisiopatología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/metabolismo , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , Cultivo Primario de Células , Ratas , Recuperación de la Función/inmunologíaRESUMEN
Immune cell infiltration to the injured brain is a key component of the neuroinflammatory response after ischemic stroke. In contrast to the large amount of proinflammatory immune cells, regulatory T cells, are an important subgroup of T cells that are involved in maintaining immune homeostasis and suppress an overshooting immune reaction after stroke. Numerous previous reports have consistently demonstrated the beneficial role of this immunosuppressive immune cell population during the acute phase after experimental stroke by limiting inflammatory lesion progression. Two recent studies expanded now this concept and demonstrate that regulatory T cells-mediated effects also promote chronic recovery after stroke by promoting a proregenerative tissue environment. These recent findings suggest that boosting regulatory T cells could be beneficial beyond modulating the immediate neuroinflammatory response and improve chronic functional recovery.
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Accidente Cerebrovascular Isquémico/inmunología , Recuperación de la Función/inmunología , Linfocitos T Reguladores/inmunología , Animales , HumanosRESUMEN
While traumatic brain injury (TBI) is the leading cause of death and disability in children, we have yet to identify those pathogenic events that determine the extent of recovery. Neutrophils are best known as "first responders" to sites of infection and trauma where they become fully activated, killing pathogens via proteases that are released during degranulation. However, this activational state may generate substantial toxicity in the young brain after TBI that is partially due to developmentally regulated inadequate antioxidant reserves. Neutrophil degranulation is triggered via a downstream signaling pathway that is dependent on spleen tyrosine kinase (Syk). To test the hypothesis that the activational state of neutrophils is a determinant of early pathogenesis and long-term recovery, we compared young, brain-injured conditional knockouts of Syk (sykf/fMRP8-cre+) to congenic littermates (sykf/f). Based upon flow cytometry, there was an extended recruitment of distinct leukocyte subsets, including Ly6G+/Ly6C- and Ly6G+/Ly6Cint, over the first several weeks post-injury which was similar between genotypes. Subsequent assessment of the acutely injured brain revealed a reduction in blood-brain barrier disruption to both high and low molecular weight dextrans and reactive oxygen species in sykf/fMRP8-cre+ mice compared to congenic littermates, and this was associated with greater preservation of claudin 5 and neuronal integrity, as determined by Western blot analyses. At adulthood, motor learning was less affected in brain-injured sykf/fMRP8-cre+ mice as compared to sykf/f mice. Performance in the Morris Water Maze revealed a robust improvement in hippocampal-dependent acquisition and short and long-term spatial memory retention in sykf/fMRP8-cre+ mice. Subsequent analyses of swim path lengths during hidden platform training and probe trials showed greater thigmotaxis in brain-injured sykf/f mice than sham sykf/f mice and injured sykf/fMRP8-cre+ mice. Our results establish the first mechanistic link between the activation state of neutrophils and long-term functional recovery after traumatic injury to the developing brain. These results also highlight Syk kinase as a novel therapeutic target that could be further developed for the brain-injured child.
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Barrera Hematoencefálica/metabolismo , Lesiones Traumáticas del Encéfalo/inmunología , Encéfalo/inmunología , Cognición , Infiltración Neutrófila/genética , Neutrófilos/inmunología , Recuperación de la Función/genética , Quinasa Syk/genética , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/fisiopatología , Aprendizaje/fisiología , Ratones , Ratones Noqueados , Prueba del Laberinto Acuático de Morris , Neuronas/patología , Infiltración Neutrófila/inmunología , Neutrófilos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Recuperación de la Función/inmunología , Memoria Espacial/fisiologíaRESUMEN
OBJECTIVES: Olfactory and gustatory dysfunction (OD/GD) are now recognized as typical symptoms of COVID-19 infection. However, their pathogenesis remains unclear and no clear prognostic factors have been identified. We have analyzed a cohort of mild/moderate hospitalized patients to identify possible clinical or immunological predictors of recovery from OD/GD. METHODS: Clinical and biological parameters were reviewed along with associated comorbidities. Chemosensory Complaint Score was administered on admission and 30 days after the first negative swab. Unpaired Wilcoxon and chi-squared tests were used to compare the variables in the patients who recovered versus those who did not. RESULTS: From a cohort of 119 hospitalized patients, 43 (36%) reported OD/GD on admission. 60.6% had a full recovery from OD and 69.2% from GD. Only the concentration of IL-10 on admission emerged as significantly associated with recovery of taste (p = 0.041) while allergic respiratory disease was more prevalent in the group who did not recover from OD (p = 0.049) and GD (p = 0.007). CONCLUSION: These findings suggest that COVID-19 associated OD/GD is an inflammatory-mediated condition and that clinical and immunological parameters could predict the evolution of these symptoms.
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COVID-19/complicaciones , COVID-19/inmunología , Interleucina-10/sangre , Trastornos del Olfato/etiología , Trastornos del Olfato/inmunología , Pandemias , SARS-CoV-2 , Trastornos del Gusto/etiología , Trastornos del Gusto/inmunología , Biomarcadores/sangre , COVID-19/sangre , Estudios de Cohortes , Femenino , Humanos , Mediadores de Inflamación/sangre , Mediadores de Inflamación/inmunología , Interleucina-10/inmunología , Masculino , Persona de Mediana Edad , Trastornos del Olfato/sangre , Pronóstico , Recuperación de la Función/inmunología , Índice de Severidad de la Enfermedad , Trastornos del Gusto/sangreRESUMEN
BACKGROUND: Persistent inflammation is an important driver of disease progression and affects prognosis. Some indicators of inflammation predict short-term outcomes. The relationship between prognosis, especially mortality, and persistent inflammation in massive stroke has not been studied, and this has been the subject of our research. METHODS: From April 1, 2017 to February 1, 2020, consecutive patients were prospectively enrolled. Clinical data, laboratory data, imaging data and follow-up infections morbidity were compared between 2 groups according to modified Rankin scale (mRS) scores (mRS < 3 and ≥ 3) at 1 month. The binomial logistic analysis was used to determine independent factors of 1-month prognosis. Short-term functional outcome, mortality and infection rates in massive stroke with and without persistent inflammation were compared. RESULTS: One hundred thirty-nine patients with massive stroke were included from 800 patients. We found that admission blood glucose levels (p = 0.005), proportions of cerebral hemispheric (p = 0.001), posterior circulatory (p = 0.035), and lacunar (p = 0.022) ischemia were higher in poor outcome patients; neutrophil-to-lymphocyte ratio (odd ratio = 1.87, 95%CI 1.14-3.07, p = 0.013) and blood glucose concentrations (odd ratio = 1.34, 95%CI 1.01-1.79, p = 0.043) can independently predict the short-term prognosis in massive stroke patients. We also found that the incidence of pulmonary infection (p = 0.009), one-month mortality (p = 0.003) and adverse outcomes (p = 0.0005) were higher in patients with persistent inflammation. CONCLUSIONS: This study suggested that persistent inflammation is associated with poor prognosis, 1-month mortality and the occurrence of in-hospital pulmonary infection and that higher baseline inflammation level predicts short-term poor outcomes in massive stroke.
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Inflamación/inmunología , Recuperación de la Función/inmunología , Accidente Cerebrovascular/inmunología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inflamación/etiología , Inflamación/mortalidad , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pronóstico , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/mortalidadRESUMEN
The role of suppressive anti-retroviral therapy (ART) in eliciting restoration of dysregulated immune function remains unclear in HIV-1 infection. Also, due to tailoring of therapeutic regimens towards HIV-1, this possible impairment of therapy may be even more pronounced in HIV-2 and dual (HIV-D) infection. Thus, we evaluated the impact of ART on immune restoration by assessing T cell functions, including HIV specific responses in HIV-1-, HIV-2- and HIV-D-infected individuals. Both ART-treated and naive infected subjects showed persistently altered frequency of CD4+ T cell subsets [regulatory T cells (Treg ), naive/central memory, effector memory], increased immune activation, cytoxicity and decreased frequency of natural killer T (NKT)- like cells and T helper type 17 (Th17)/Treg ratio with elevated microbial translocation. Further, HIV-specific responses were dominated by gag-specific CD4+ T cells in virologically suppressed HIV-D individuals, suggesting retention of T cell memory for both viruses. Increased antigen-specific responses, including dual-functional interleukin (IL)-2/interferon (IFN)-γ CD4+ T cells, were detected in therapy receiving HIV-2-infected individuals indicative of a greater and more functionally diverse T cell memory repertoire. We delineated immune signatures specific to therapy-naive single HIV infection, as well as a unique signature associated with HIV-2 disease progression and immune restoration. Circulating Treg frequency, T cell activation and microbial translocation levels correlated with disease progression and immune restoration among all types of HIV infection. Also, memory responses negatively correlated, irrespective of type of infection, in ART receiving infected individuals, with CD4 rebound and decreased pan T cell activation. Our data highlight the need for adjunct immunomodulatory therapeutic strategies to achieve optimal immune restoration in HIV infection.
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Infecciones por VIH/inmunología , VIH-1/inmunología , VIH-2/inmunología , Memoria Inmunológica , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adulto , Progresión de la Enfermedad , Femenino , Infecciones por VIH/patología , Humanos , Interferón gamma/inmunología , Interleucina-2/inmunología , Masculino , Persona de Mediana Edad , Recuperación de la Función/inmunología , Linfocitos T Reguladores/patología , Células Th17/patologíaRESUMEN
Initial studies suggest that increased age is associated with worse outcomes after traumatic brain injury (TBI), though the pathophysiological mechanisms responsible for this remain unclear. Immunosenescence (i.e., dysregulation of the immune system due to aging) may play a significant role in influencing TBI outcomes. This study therefore examined neurological outcomes and immune response in young-adult (i.e., 10â¯weeks old) compared to middle-aged (i.e., 1â¯year old) rats following a TBI (i.e., fluid percussion) or sham-injury. Rats were euthanized at either 24â¯h or one-week post-injury to analyze immune cell populations in the brain and periphery via flow cytometry, as well as telomere length (i.e., a biomarker of neurological health). Behavioral testing, as well as volumetric and diffusion-weighted MRI, were also performed in the one-week recovery rats to assess for functional deficits and brain damage. Middle-aged rats had worse sensorimotor deficits and shorter telomeres after TBI compared to young rats. Both aging and TBI independently worsened cognitive function and cortical volume. These changes occurred in the presence of fewer total leukocytes, fewer infiltrating myeloid cells, and fewer microglia in the brains of middle-aged TBI rats compared to young rats. These findings indicate that middle-aged rats have worse sensorimotor deficits and shorter telomeres after TBI than young rats, and this may be related to an altered neuroimmune response. Although further studies are required, these findings have important implications for understanding the pathophysiology and optimal treatment strategies in TBI patients across the life span.
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Lesiones Traumáticas del Encéfalo/inmunología , Neuroinmunomodulación/inmunología , Recuperación de la Función/inmunología , Factores de Edad , Animales , Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/metabolismo , Cognición/fisiología , Trastornos del Conocimiento/complicaciones , Modelos Animales de Enfermedad , Masculino , Microglía/inmunología , Microglía/metabolismo , Ratas , Ratas Wistar , Recuperación de la Función/fisiología , Homeostasis del Telómero/inmunología , Resultado del TratamientoRESUMEN
Our first ever Open Highlights explores recent Open Access research into the complex relationship between host and pathogen during the course of an infection, and the factors that determine its eventual outcome.
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Adaptación Fisiológica/inmunología , Resistencia a la Enfermedad/inmunología , Tolerancia Inmunológica/inmunología , Inmunidad Innata/inmunología , Animales , Interacciones Huésped-Patógeno/inmunología , Humanos , Modelos Inmunológicos , Recuperación de la Función/inmunología , Recuperación de la Función/fisiologíaRESUMEN
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of (non) malignant conditions. GvHD is a severe complication with high morbidity and mortality. The pathogenesis remains unclear. We studied dendritic cell (DC) reconstitution to detect potential differences, which may improve our knowledge in the development of chronic GvHD (cGvHD). PROCEDURE: We examined immune reconstitution (T, B, and NK cells and dendritic cells) at defined time points in a pediatric cohort who underwent 61 allogeneic HSCTs. RESULTS: Regarding DC reconstitution we found a fast reconstitution of the DC compartment negatively correlated with age. After HSCT, both myeloid DC (mDC) and plasmacytoid DC (pDC) counts recover to pre-HSCT levels within 2 months. Higher CCR7 positive cell counts were found in patients receiving TBI during engraftment and during the whole posttransplant period we found a correlation with an improved outcome. In cGVHD patients decreased total DC counts and increased pDCs were found after day+100. No relevant correlation was achieved regarding to HLA-matching, stem cell manipulation of the graft as well as HSCT-indication compared with different DC counts. DISCUSSION: Pathogenesis of cGvHD remains complex. Our data suggest an influence of dendritic cells, which may contribute to the clinical picture and should be further investigated in future studies.
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Células Dendríticas/inmunología , Trasplante de Células Madre Hematopoyéticas , Recuperación de la Función/inmunología , Adolescente , Aloinjertos , Niño , Preescolar , Enfermedad Crónica , Células Dendríticas/patología , Femenino , Humanos , Linfocitos/inmunología , Linfocitos/patología , MasculinoRESUMEN
PURPOSE: Alterations in immunological homeostasis induced by acute exercise have been frequently reported. In view of the growing amount of repetitive exercise stimuli in competitive sports, quick recovery plays a superior role. Therefore, we examined whether aqua cycling affects cellular immunological recovery. METHODS: After performing 300 countermovement jumps with maximal effort male sport students (n = 20; 24.4 ± 2.2 years) were randomized into either an aqua cycling (AC) or a passive recovery (P) group. AC pedaled in chest-deep water without resistance, while P lay in a supine position. Each recovery protocols lasted 30 min. Blood samples were taken at Baseline, Post-exercise, Post-recovery and 1 h (h), 2 h, 4 h, 24 h, 48 h and 72 h after recovery. Outcomes comprised white blood cell (WBC) counts, lymphocyte (LYM) counts and LYM subsets (CD4/CD8 ratio). Additionally, cellular inflammation markers (neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII)) were calculated. RESULTS: In both groups, WBC, NLR and SII were significantly increased compared to Baseline up to and including 4 h after recovery. Significant interaction effects were found for WBC (Post-recovery, 2 h and 4 h), NLR (Post-recovery), SII (Post-recovery) and CD4/CD8 ratio (2 h) with values of AC being higher than of P. CONCLUSIONS: Interestingly, AC provoked a stronger but not prolonged immunological disturbance than P. NLR and SII may present simple, more integrative markers to screen exercise-induced alterations in immune homeostasis/recovery in athletes and clinical populations. More research is warranted to elucidate the clinical and practical relevance of these findings.
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Terapia por Ejercicio/métodos , Acondicionamiento Físico Humano/métodos , Esfuerzo Físico/inmunología , Recuperación de la Función/inmunología , Adulto , Relación CD4-CD8 , Humanos , Masculino , Acondicionamiento Físico Humano/efectos adversos , Recuento de PlaquetasRESUMEN
Outcomes for patients with high-risk neuroblastoma (HR-NBL) are significantly improved with the addition of immunotherapy (dinutuximab + cytokines) following autologous hematopoietic stem cell transplantation (auto-HSCT). We hypothesized that the immune system is not fully reconstituted at the initiation of immunotherapy. To test this hypothesis, we evaluated hematologic and immune subsets in 34 patients with HR-NBL before and after auto-HSCT. We found that absolute T, B, and NK cell counts at the time of immunotherapy were below normal in 80% of patients. Patients with residual disease at the time of transplantation had significantly lower absolute lymphocyte counts (ALC; P = .008), lower CD16+ cell counts (P = .009), and an abnormal ratio of cytokine-releasing to cytotoxic NK cells at the time of dinutuximab treatment. In addition, the preparative regimen used for auto-HSCT predicted immune recovery. Finally, higher total white blood cell count (P = .013) and ALC (P = .013) at 3 months after completion of therapy were measured in patients who remained in remission compared with those who relapsed. Our results indicate that most patients with HR-NBL do not have full immune reconstitution at the time of dinutuximab treatment after auto-HSCT, and that immune recovery may correlate with disease-related outcomes in patients with high-risk disease.
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Anticuerpos Monoclonales/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Inmunoterapia , Neuroblastoma/inmunología , Neuroblastoma/terapia , Recuperación de la Función/inmunología , Adolescente , Adulto , Autoinjertos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neuroblastoma/patología , Estudios RetrospectivosRESUMEN
PURPOSE OF REVIEW: In adult mammals, a traumatic spinal cord injury (SCI) elicits a chronic unregulated neuroinflammatory response accompanied by seemingly paradoxical suppression of systemic immunity. These SCI-induced changes in immune function contribute to poor neurological outcomes and enhanced morbidity or mortality. Nonspecific anti-inflammatory or proinflammatory therapies are ineffective and can even worsen outcomes. Therefore, recent experimental SCI research has advanced the understanding of how neuroimmune cross-talk contributes to spinal cord and systemic pathology. RECENT FINDINGS: It is now appreciated that the immune response caused by injury to the brain or spinal cord encompasses heterogeneous elements that can drive events on the spectrum between exacerbating pathology and promoting tissue repair, within the spinal cord and throughout the body. Recent novel discoveries regarding the role and regulation of soluble factors, monocytes/macrophages, microRNAs, lymphocytes and systemic immune function are highlighted in this review. SUMMARY: A more nuanced understanding of how the immune system responds and reacts to nervous system injury will present an array of novel therapeutic opportunities for clinical SCI and other forms of neurotrauma.
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Encéfalo/inmunología , Recuperación de la Función/inmunología , Traumatismos de la Médula Espinal/inmunología , Médula Espinal/inmunología , Animales , Humanos , MicroARNsRESUMEN
Hydrogen sulfide (H2S) is an endogenous gasotransmitter that has vasodilatory properties. It may be a novel therapy for intestinal ischemia-reperfusion (I/R) injury. We hypothesized that 1) H2S would improve postischemic survival, mesenteric perfusion, mucosal injury, and inflammation compared with vehicle and 2) the benefits of H2S would be mediated through endothelial nitric oxide. C57BL/6J wild-type and endothelial nitric oxide synthase knockout (eNOS KO) mice were anesthetized, and a midline laparotomy was performed. Intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using laser Doppler. Intestinal ischemia was established by temporarily occluding the superior mesenteric artery. Following ischemia, the clamp was removed, and the intestines were allowed to recover. Either sodium hydrosulfide (2 nmol/kg or 2 µmol/kg NaHS) in PBS vehicle or vehicle only was injected into the peritoneum. Animals were allowed to recover and were assessed for mesenteric perfusion, mucosal injury, and intestinal cytokines. P values < 0.05 were significant. H2S improved mesenteric perfusion and mucosal injury scores following I/R injury. However, in the setting of eNOS ablation, there was no improvement in these parameters with H2S therapy. Application of H2S also resulted in lower levels of intestinal cytokine production following I/R. Intraperitoneal H2S therapy can improve mesenteric perfusion, intestinal mucosal injury, and intestinal inflammation following I/R. The benefits of H2S appear to be mediated through endothelial nitric oxide-dependent pathways.NEW & NOTEWORTHY H2S is a gaseous mediator that acts as an anti-inflammatory agent contributing to gastrointestinal mucosal defense. It promotes vascular dilation, mucosal repair, and resolution of inflammation following intestinal ischemia and may be exploited as a novel therapeutic agent. It is unclear whether H2S works through nitric oxide-dependent pathways in the intestine. We appreciate that H2S was able to improve postischemic recovery of mesenteric perfusion, mucosal integrity, and inflammation. The beneficial effects of H2S appear to be mediated through endothelial nitric oxide-dependent pathways.
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Sulfuro de Hidrógeno/administración & dosificación , Intestinos/irrigación sanguínea , Intestinos/inmunología , Óxido Nítrico/inmunología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/inmunología , Animales , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inmunología , Gasotransmisores/administración & dosificación , Intestinos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Resultado del TratamientoRESUMEN
Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after the resolution of sepsis. Therefore, the signaling pathways governing protein synthesis, autophagy, apoptosis, and the ubiquitin-proteasome were investigated to identify potential mechanisms mediating the acute (24 h) loss of WAT after cecal ligation and puncture as well as the failure to replenish WAT during recovery (day 10). While whole body fat mass was decreased equally in pair-fed control and septic mice at 5 days after cecal ligation and puncture, fat mass remained 35% lower in septic mice at day 10 During sepsis-recovery, protein synthesis in epididymal WAT was increased compared with control values, and this increase was associated with an elevation in eukaryotic translation initiation factor (eIF)2Bε but no change in mammalian target of rapamycin complex 1 activity (eIF4E-binding protein-1 or S6 kinase 1 phosphorylation). Protein breakdown was increased during sepsis-recovery, as evidenced by the elevation in ubiquitin-proteasome activity. Moreover, indexes of autophagy (light chain 3B-II, autophagy-related protein 5/12, and beclin) were increased during sepsis-recovery and associated with increased AMP-activated kinase-dependent Ser555-phosphorylated Unc-51-like autophagy activating kinase-1. Apoptosis was increased, as suggested by the increased cleavage of caspase-3 and poly(ADP-ribose) polymerase. These changes were associated with increased inflammasome activity (increased NLR family, pyrin domain containing 3; TMS1; and caspase-1 cleavage) and the endoplasmic reticulum stress response (increased eIF2α and activating transcription factor-4) and browning (uncoupling protein-1) in epididymal WAT. Our data suggest that WAT stores remain depleted during recovery from sepsis due to sustained inflammation and elevations in protein and cellular degradation, despite the increase in protein synthesis.
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Tejido Adiposo Blanco/inmunología , Apoptosis/inmunología , Autofagia/inmunología , Complejo de la Endopetidasa Proteasomal/inmunología , Recuperación de la Función/inmunología , Sepsis/inmunología , Tejido Adiposo Blanco/patología , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Objective: To study disease severity and response to therapy in a large cohort of patients with anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)-associated myositis. Methods: Muscle strength, creatine kinase levels and treatments were assessed in anti-HMGCR-positive patients at each clinical visit. Univariate and multivariate analyses were used to analyse the influence of clinical characteristics on strength and the change in strength over time. Whole exome sequencing was performed in a subset of patients. Results: . Among 50 patients followed for ⩾2 years, only 22 (44%) reached full strength with immunosuppressive therapy; even among those with full strength, 55% continued to have CK levels in excess of 500 IU/l and only three could be tapered off immunosuppressive therapy. Both univariate and multivariate analysis showed that patients who were older at disease onset were stronger at all time points (P < 0.001) and improved faster (P < 0.008) than younger patients; a history of statin exposure was not independently associated with the improvement rate. Younger patients were more likely to have refractory disease (P = 0.02) than older patients. Among eight refractory patients with DNA available for testing, whole exome sequencing did not reveal pathogenic mutations in known dystrophy genes. The risk of cancer was not increased in anti-HMGCR myositis patients compared with the general population. Conclusions: Anti-HMGCR myositis is usually a chronic disease requiring long-term immunosuppression. Although younger patients had more severe disease and a worse prognosis than older patients, they did not have evidence of a known co-existing muscular dystrophy to explain their persistent, and sometimes progressive, muscle weakness.
Asunto(s)
Enfermedades Autoinmunes/enzimología , Hidroximetilglutaril-CoA Reductasas/inmunología , Miositis/enzimología , Adolescente , Adulto , Cuidados Posteriores , Edad de Inicio , Anciano , Anciano de 80 o más Años , Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/inmunología , Niño , Preescolar , Creatina Quinasa/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fuerza Muscular/inmunología , Fuerza Muscular/fisiología , Debilidad Muscular/enzimología , Debilidad Muscular/inmunología , Músculo Esquelético/enzimología , Músculo Esquelético/inmunología , Miositis/inmunología , Miositis/terapia , Neoplasias/enzimología , Neoplasias/inmunología , Pronóstico , Recuperación de la Función/inmunología , Recuperación de la Función/fisiología , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.
Asunto(s)
Linfocitos B , Inmunidad Humoral/efectos de los fármacos , Inmunoglobulinas , Infecciones , Leucemia Linfocítica Crónica de Células B , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Recuperación de la Función , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , Linfocitos B/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulinas/sangre , Inmunoglobulinas/inmunología , Infecciones/sangre , Infecciones/tratamiento farmacológico , Infecciones/inmunología , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Piperidinas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/inmunología , Proteínas Tirosina Quinasas/metabolismo , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/inmunología , Factores de TiempoRESUMEN
Anemia of inflammation (AI) is commonly observed in chronic inflammatory states and may hinder patient recovery and survival. Induction of hepcidin, mediated by interleukin 6, leads to iron-restricted erythropoiesis and anemia. Several translational studies have been directed at neutralizing hepcidin overexpression as a therapeutic strategy against AI. However, additional hepcidin-independent mechanisms contribute to AI, which are likely mediated by a direct effect of inflammatory cytokines on erythropoiesis. In this study, we used wild-type, hepcidin knockout (Hamp-KO) and interleukin 6 knockout (IL-6-KO) mice as models of AI. AI was induced with heat-killed Brucella abortus (BA). The distinct roles of iron metabolism and inflammation triggered by interleukin 6 and hepcidin were investigated. BA-treated wild-type mice showed increased expression of hepcidin and inflammatory cytokines, as well as transitory suppression of erythropoiesis and shortened red blood cell lifespan, all of which contributed to the severe anemia of these mice. In contrast, BA-treated Hamp-KO or IL-6-KO mice showed milder anemia and faster recovery compared with normal mice. Moreover, they exhibited different patterns in the development and resolution of anemia, supporting the notion that interleukin 6 and hepcidin play distinct roles in modulating erythropoiesis in AI.
Asunto(s)
Anemia/inmunología , Brucella abortus , Brucelosis/inmunología , Hepcidinas/inmunología , Interleucina-6/inmunología , Anemia/genética , Anemia/microbiología , Animales , Médula Ósea/inmunología , Brucelosis/complicaciones , Modelos Animales de Enfermedad , Eritropoyesis/inmunología , Femenino , Hepcidinas/genética , Calor , Interleucina-6/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Recuperación de la Función/inmunologíaRESUMEN
Traumatic brain injury (TBI) is the leading cause of disability and death in young adults. The secondary neuroinflammation and neuronal damage that follows the primary mechanical injury is an important cause of disability in affected people. The membrane attack complex (MAC) of the complement system is detected in the traumatized brain early after TBI; however, its role in the pathology and neurologic outcome of TBI has not yet been investigated. We generated a C6 antisense oligonucleotide that blocks MAC formation by inhibiting C6, and we compared its therapeutic effect to that of Ornithodoros moubata complement inhibitor (OmCI), a known inhibitor of C5 activation that blocks generation of the anaphylatoxin C5a and C5b, an essential component of MAC. Severe closed head injury in mice induced abundant MAC deposition in the brain. Treatment with C6 antisense reduced C6 synthesis (85%) and serum levels (90%), and inhibited MAC deposition in the injured brain (91-96%). Treatment also reduced accumulation of microglia/macrophages (50-88%), neuronal apoptosis, axonal loss and weight loss (54-93%), and enhanced neurologic performance (84-92%) compared with placebo-treated controls after injury. These data provide the first evidence, to our knowledge, that inhibition of MAC formation in otherwise complement-sufficient animals reduces neuropathology and promotes neurologic recovery after TBI. Given the importance of maintaining a functional complement opsonization system to fight infections, a critical complication in TBI patients, inhibition of the MAC should be considered to reduce posttraumatic neurologic damage. This work identifies a novel therapeutic target for TBI and will guide the development of new therapy for patients.
Asunto(s)
Proteínas de Artrópodos/farmacología , Axones/inmunología , Lesiones Encefálicas/tratamiento farmacológico , Proteínas Portadoras/farmacología , Complejo de Ataque a Membrana del Sistema Complemento/antagonistas & inhibidores , Macrófagos/inmunología , Oligodesoxirribonucleótidos Antisentido/farmacología , Animales , Axones/patología , Lesiones Encefálicas/inmunología , Lesiones Encefálicas/patología , Complemento C5a/antagonistas & inhibidores , Complemento C5a/inmunología , Complemento C5b/antagonistas & inhibidores , Complemento C5b/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Femenino , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Microglía/inmunología , Microglía/patología , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/inmunologíaRESUMEN
The mucosa that lines the respiratory and gastrointestinal (GI) tracts is an important portal of entry for pathogens and provides the first line of innate immune defense against infections. Although an abundance of memory CD4(+) T cells at mucosal sites render them highly susceptible to HIV infection, the gut and not the lung experiences severe and sustained CD4(+) T cell depletion and tissue disruption. We hypothesized that distinct immune responses in the lung and gut during the primary and chronic stages of viral infection contribute to these differences. Using the SIV model of AIDS, we performed a comparative analysis of the molecular and cellular characteristics of host responses in the gut and lung. Our findings showed that both mucosal compartments harbor similar percentages of memory CD4(+) T cells and displayed comparable cytokine (IL-2, IFN-γ, and TNF-α) responses to mitogenic stimulations prior to infection. However, despite similar viral replication and CD4(+) T cell depletion during primary SIV infection, CD4(+) T cell restoration kinetics in the lung and gut diverged during acute viral infection. The CD4(+) T cells rebounded or were preserved in the lung mucosa during chronic viral infection, which correlated with heightened induction of type I IFN signaling molecules and innate viral restriction factors. In contrast, the lack of CD4(+) T cell restoration in the gut was associated with dampened immune responses and diminished expression of viral restriction factors. Thus, unique immune mechanisms contribute to the differential response and protection of pulmonary versus GI mucosa and can be leveraged to enhance mucosal recovery.