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1.
Transl Res ; 2019 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-31794697

RESUMEN

Glomerular endothelial cell (GEC) dysfunction occurs in diabetic kidney disease (DKD) and generally precedes albuminuria. We recently reported that hedgehog interacting protein (Hhip), highly expressed in GECs, contributes to DKD development in diabetic mice. Here, we hypothesized that urinary Hhip (uHhip) could identify early DKD; we tested uHhip in mice and humans with diabetes (DM). In both type 1 (Akita) and type 2 (db/db) DM mice, uHhip is elevated prior to the development of albuminuria, while non-DM controls excrete minimal amount of uHhip. In 87 type 2 DM patients and 39 healthy controls, the uHhip/creatinine (Cr) ratio provides a significant discrimination between non-DM and DM groups; 0 [0-69.5] in non-DM, 9.9 [1.7-39.5] in normoalbuminuric DM, 167.7 [95.7-558.7] in microalbuminuric DM, and 207.9 [0-957.2] in macroalbuminuric DM (median [IQR] ng/mmol, P < 0.0001). The log-uHhip/Cr is positively correlated with urine albumin/Cr ratio (UACR) (spearman correlation coefficient 0.47, P < 0.0001). The log-uHhip/Cr is also associated with eGFR, pulse pressure, and urinary cytokines (IL-1ß, IL-6, IL-8, and TGFß1) independent of UACR. By immunostaining, Hhip is localized in glomeruli and tubules, and is increased in human DM kidneys compared with non-DM kidneys. TGFß1 shares the similar staining pattern as Hhip in human DM kidneys. Thus, uHhip appears to be a novel indicator of diabetic GEC injury and is elevated in early DKD before the development of microalbuminuria in mice and humans. Clinical value for detecting early DKD warrants further investigation.

2.
J Neuroinflammation ; 16(1): 253, 2019 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-31801576

RESUMEN

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Inflammation is induced following SAH, but the exact role and phenotype of innate immune cells remain poorly characterized. We investigated the inflammatory components of the early brain injury in an animal model and in SAH patients. METHOD: SAH was induced through injection of blood in the subarachnoid space of C57Bl/6 J wild-type mice. Prospective blood collections were obtained at 12 h, days 1, 2, and 7 to evaluate the systemic inflammatory consequences of SAH by flow cytometry and enzyme-linked immunosorbent-assay (ELISA). Brains were collected, enzymatically digested, or fixed to characterize infiltrating inflammatory cells and neuronal death using flow cytometry and immunofluorescence. Phenotypic evaluation was performed at day 7 using the holding time and footprint tests. We then compared the identified inflammatory proteins to the profiles obtained from the plasma of 13 human SAH patients. RESULTS: Following SAH, systemic IL-6 levels increased rapidly, whereas IL-10 levels were reduced. Neutrophils were increased both in the brain and in the blood reflecting local and peripheral inflammation following SAH. More intracerebral pro-inflammatory monocytes were found at early time points. Astrocyte and microglia activation were also increased, and mice had severe motor deficits, which were associated with an increase in the percentage of caspase-3-positive apoptotic neurons. Similarly, we found that IL-6 levels in patients were rapidly increased following SAH. ICAM-1, bFGF, IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes. Moreover, high levels of Flt-1 and VEGF at admission were associated with worse outcomes. CONCLUSION: SAH induces an early intracerebral infiltration and peripheral activation of innate immune cells. Furthermore, microglia and astrocytic activation are present at later time points. Our human and mouse data illustrate that SAH is a systemic inflammatory disease and that immune cells represent potential therapeutic targets to help this population of patients in need of new treatments.

3.
Nat Commun ; 10(1): 4712, 2019 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-31624262

RESUMEN

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.


Asunto(s)
Trasplante de Riñón/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Femenino , Rechazo de Injerto/inmunología , Humanos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/inmunología , Fallo Renal Crónico/terapia , Melanoma/inmunología , Melanoma/terapia , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Tolerancia al Trasplante/efectos de los fármacos , Tolerancia al Trasplante/inmunología
4.
Artículo en Inglés | MEDLINE | ID: mdl-31476146

RESUMEN

BACKGROUND: An enhanced inflammatory response is a trigger to the production of blood macromolecules involved in abnormally high levels of erythrocyte aggregation. OBJECTIVE: This study aimed at demonstrating for the first time the clinical feasibility of a non-invasive ultrasound-based erythrocyte aggregation quantitative measurement method for potential application in critical care medicine. METHODS: Erythrocyte aggregation was evaluated using modeling of the backscatter coefficient with the Structure Factor Size and Attenuation Estimator (SFSAE). SFSAE spectral parameters W (packing factor) and D (mean aggregate diameter) were measured within the antebrachial vein of the forearm and tibial vein of the leg in 50 healthy participants at natural flow and reduced flow controlled by a pressurized bracelet. Blood samples were also collected to measure erythrocyte aggregation ex vivo with an erythroaggregometer (parameter S10). RESULTS: W and Din vivo measurements were positively correlated with the ex vivoS10 index for both measurement sites and shear rates (correlations between 0.35-0.81, p <  0.05). Measurement at low shear rate was found to increase the sensitivity and reliability of this non-invasive measurement method. CONCLUSIONS: We behold that the SFSAE method presents systemic measures of the erythrocyte aggregation level, since results on upper and lower limbs were highly correlated.

5.
J Clin Invest ; 129(6): 2463-2479, 2019 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-30912767

RESUMEN

Rationale Tumor infiltrating lymphocytes are widely associated with positive outcomes, yet carry key indicators of a systemic failed immune response against unresolved cancer. Cancer immunotherapies can reverse their tolerance phenotypes, while preserving tumor-reactivity and neoantigen-specificity shared with circulating immune cells. Objectives We performed comprehensive transcriptomic analyses to identify gene signatures common to circulating and tumor infiltrating lymphocytes in the context of clear cell renal cell carcinoma. Modulated genes also associated with disease outcome were validated in other cancer types. Findings Using bioinformatics, we identified practical diagnostic markers and actionable targets of the failed immune response. On circulating lymphocytes, three genes, LEF1, FASLG, and MMP9, could efficiently stratify patients from healthy control donors. From their associations with resistance to cancer immunotherapies and microbial infections, we uncovered not only pan-cancer, but pan-pathology failed immune response profiles. A prominent lymphocytic matrix metallopeptidase cell migration pathway, is central to a panoply of diseases and tumor immunogenicity, correlates with multi-cancer recurrence, and identifies a feasible, non-invasive approach to pan-pathology diagnoses. Conclusions The non-invasive differently expressed genes we have identified warrant future investigation towards the development of their potential in precision diagnostics and precision pan-disease immunotherapeutics.

6.
Clin J Am Soc Nephrol ; 14(4): 496-505, 2019 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-30898872

RESUMEN

BACKGROUND AND OBJECTIVES: Older patients in the intensive care unit are at greater risk of AKI; however, use of kidney replacement therapy in this population is poorly characterized. We describe the triggers and outcomes associated with kidney replacement therapy in older patients with AKI in the intensive care unit. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a prospective cohort study in 16 Canadian hospitals from September 2013 to November 2015. Patients were ≥65 years old, were critically ill, and had severe AKI; exclusion criteria were urgent kidney replacement therapy for a toxin and ESKD. We recorded triggers for kidney replacement therapy (primary exposure), reasons for not receiving kidney replacement therapy, 90-day mortality (primary outcome), and kidney recovery. RESULTS: Of 499 patients, mean (SD) age was 75 (7) years old, Charlson comorbidity score was 3.0 (2.3), and median (interquartile range) Clinical Frailty Scale score was 4 (3-5). Most were receiving mechanical ventilation (64%; n=319) and vasoactive support (63%; n=314). Clinicians were willing to offer kidney replacement therapy to 361 (72%) patients, and 229 (46%) received kidney replacement therapy. Main triggers for kidney replacement therapy were oligoanuria, fluid overload, and acidemia, whereas main reasons for not receiving therapy were anticipated recovery (67%; n=181) and therapy not consistent with patient preferences for care (24%; n=66). Ninety-day mortality was similar in patients who did and did not receive kidney replacement therapy (50% versus 51%; adjusted hazard ratio, 0.78; 95% confidence interval, 0.58 to 1.06); however, decisions to offer kidney replacement therapy varied significantly by patient mix, acuity, and perceived benefit. There were no differences in health-related quality of life or rehospitalization among survivors. CONCLUSIONS: Most older, critically ill patients with severe AKI were perceived as candidates for kidney replacement therapy, and approximately one half received therapy. Both willingness to offer kidney replacement therapy and reasons for not starting showed heterogeneity due to a range in patient-specific factors and clinician perceptions of benefit.

7.
Am J Transplant ; 19(3): 699-712, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30129231

RESUMEN

Autoantibodies against perlecan/LG3 (anti-LG3) have been associated with increased risks of delayed graft function, acute rejection, and reduced long-term survival. High titers of anti-LG3 antibodies have been found in de novo renal transplants recipients in the absence of allosensitizing or autoimmune conditions. Here, we seek to understand the pathways controlling anti-LG3 production prior to transplantation. Mice immunized with recombinant LG3 produce concomitantly IgM and IgG anti-LG3 antibodies suggesting a memory response. ELISpot confirmed the presence of LG3-specific memory B cells in nonimmunized mice. Purification of B1 and B2 subtypes identified peritoneal B1 cells as the major source of memory B cells reactive to LG3. Although nonimmunized CD4-deficient mice were found to express LG3-specific memory B cells, depletion of CD4+ T cells in wild type mice during immunization significantly decreased anti-LG3 production. These results demonstrate that B cell memory to LG3 is T cell independent but that production of anti-LG3 antibodies requires T cell help. Further supporting an important role for T cells in controlling anti-LG3 levels, we found that human renal transplant recipients show a significant decrease in anti-LG3 titers upon the initiation of CNI-based immunosuppression. Collectively, these results identify T cell targeting interventions as a means of reducing anti-LG3 levels in renal transplant patients.

8.
Can J Kidney Health Dis ; 5: 2054358118801012, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30302268

RESUMEN

Rationale: Acute kidney injury (AKI) is a frequent complication after liver transplantation. In some patients, prompt intervention targeted at a specific etiology is of paramount importance. Presenting concerns of the patients: A 25 years old man with advanced liver cirrhosis caused by sclerosing cholangitis and autoimmune hepatitis underwent orthotopic liver transplantation. One month after surgery, severe AKI developed in conjunction with recurrent ascites and lower extremity edema. Notable clinical findings included a persistently low urinary sodium excretion, a bland urinary sediment, and an abnormally monophasic hepatic vein waveform on Doppler ultrasound. Diagnoses: Inferior vena cava stenosis. Interventions: Angioplasty with stent installation. Outcomes: Rapid improvement of renal function after stent installation. Lessons learned: The following case illustrates the importance of integrating clinical cues, ultrasound features, and laboratory findings. The combination of AKI associated with lower extremity edema, abnormal monophasic hepatic vein flow on Doppler ultrasound, and a low urinary sodium excretion after liver transplantation should evoke the possibility of inferior vena cava stenosis as the etiologic factor.

9.
Ultrasound Med Biol ; 44(7): 1303-1317, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29661483

RESUMEN

This systematic review is aimed at answering two questions: (i) Is erythrocyte aggregation a useful biomarker in assessing systemic inflammation? (ii) Does quantitative ultrasound imaging provide the non-invasive option to measure erythrocyte aggregation in real time? The search was executed through bibliographic electronic databases CINAHL, EMB Review, EMBASE, MEDLINE, PubMed and the grey literature. The majority of studies correlated elevated erythrocyte aggregation with inflammatory blood markers for several pathologic states. Some studies used "erythrocyte aggregation" as an established marker of systemic inflammation. There were limited but promising articles regarding the use of quantitative ultrasound spectroscopy to monitor erythrocyte aggregation. Similarly, there were limited studies that used other ultrasound techniques to measure systemic inflammation. The quantitative measurement of erythrocyte aggregation has the potential to be a routine clinical marker of inflammation as it can reflect the cumulative inflammatory dynamics in vivo, is relatively simple to measure, is cost-effective and has a rapid turnaround time. Technologies like quantitative ultrasound spectroscopy that can measure erythrocyte aggregation non-invasively and in real time may offer the advantage of continuous monitoring of the inflammation state and, thus, may help in rapid decision making in a critical care setup.


Asunto(s)
Vasos Sanguíneos/diagnóstico por imagen , Agregación Eritrocitaria , Inflamación/sangre , Ultrasonografía/métodos , Biomarcadores/sangre , Estudios de Evaluación como Asunto , Humanos
10.
J Immunother Cancer ; 5(1): 83, 2017 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-29157311

RESUMEN

BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a significant proportion of patients with metastatic melanoma. New approaches to increase survival and to predict which patients will benefit from treatment are needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP) to assess its safety, efficacy, and to search for peripheral and tumor-based predictive biomarkers. METHODS: Thirty patients with untreated unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse events (AEs) were monitored and response to treatment was evaluated. Tumor tissue and peripheral blood were collected at specified time points to characterize tumor immune markers by immunohistochemistry and systemic immune activity by multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed. Best Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%, respectively. Median overall survival was 16.2 months. Response to treatment was positively correlated with a higher tumor CD3+ infiltrate (immune score) at baseline. NRAS and BRAF mutations were less frequent in patients who experienced clinical benefit. Assessment of peripheral blood revealed that non-responders had elevated baseline levels of CXCL8 and CCL4, and a higher proportion of circulating late differentiated B cells. Pre-existing high levels of chemokines (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly associated with worse patient overall survival. Elevated proportions of circulating CD8+/PD-1+ T cells during treatment were associated with worse survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment. A pre-existing systemic inflammatory state characterized by elevation of selected chemokines and advanced B cell differentiation, was strongly associated with poor patient outcomes, revealing potential predictive circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 , registered on August 29, 2012.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Paclitaxel/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carboplatino/farmacología , Femenino , Humanos , Ipilimumab/farmacología , Masculino , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/farmacología , Neoplasias Cutáneas/patología , Resultado del Tratamiento
11.
J Invest Dermatol ; 137(9): 2005-2013, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28526301

RESUMEN

Macrophages are essential for tissue repair. They have a crucial role in cutaneous wound healing, participating actively in the inflammation phase of the process. Unregulated macrophage activation may, however, represent a source of excessive inflammation, leading to abnormal wound healing and hypertrophic scars. Our research group has shown that apoptotic endothelial and epithelial cells secrete MFG-E8, which has the ability to reprogram macrophages from an M1 (proinflammatory) to an M2 (anti-inflammatory, pro-repair) phenotype. Hence, we tested whether modulation of macrophage reprogramming would promote tissue repair. Using a mouse model of wound healing, we showed that the presence and/or addition of MFG-E8 favors wound closure associated with an increase in CD206-positive cells and basic fibroblast growth factor production in healing tissues. More importantly, adoptive transfer of ex vivo MFG-E8-treated macrophages promoted wound closure. We also observed that MFG-E8-treated macrophages produced basic fibroblast growth factor that is responsible for fibroblast migration and proliferation. Taken together, our results strongly suggest that MFG-E8 plays a key role in macrophage reprogramming in tissue healing through induction of an anti-inflammatory M2 phenotype and basic fibroblast growth factor production, leading to fibroblast migration and wound closure.


Asunto(s)
Antígenos de Superficie/metabolismo , Apoptosis/fisiología , Proteínas de la Leche/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Cicatrización de Heridas/fisiología , Animales , Movimiento Celular , Células Cultivadas , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fagocitosis , Distribución Aleatoria , Heridas y Traumatismos/metabolismo , Heridas y Traumatismos/patología
12.
Diabetes ; 66(7): 1964-1978, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28424160

RESUMEN

We investigated the mechanism of heterogeneous nuclear ribonucleoprotein F (hnRNP F) renoprotective action in a type 2 diabetes (T2D) mouse model (db/db). Immortalized rat renal proximal tubular cells (IRPTCs) and kidneys from humans with T2D were also studied. The db/db mice developed hyperglycemia, oxidative stress, and nephropathy at age 20 weeks compared with their db/m littermates. These abnormalities, with the exception of hyperglycemia, were attenuated in db/dbhnRNP F-transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs. Sirtuin-1, Foxo3α, and catalase expression were significantly decreased in RPTCs from db/db mice and normalized in db/dbhnRNP F-Tg mice. In vitro, hnRNP F overexpression stimulated Sirtuin-1 and Foxo3α with downregulation of acetylated p53 expression and prevented downregulation of Sirtuin-1 and Foxo3α expression in IRPTCs by high glucose plus palmitate. Transfection of Sirtuin-1 small interfering RNA prevented hnRNP F stimulation of Foxo3α and downregulation of acetylated p53 expression. hnRNP F stimulated Sirtuin-1 transcription via hnRNP F-responsive element in the Sirtuin-1 promoter. Human T2D kidneys exhibited more RPTC apoptosis and lower expression of hnRNP F, SIRTUIN-1, and FOXO3α than nondiabetic kidneys. Our results demonstrate that hnRNP F protects kidneys against oxidative stress and nephropathy via stimulation of Sirtuin-1 expression and signaling in diabetes.


Asunto(s)
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/genética , Túbulos Renales Proximales/metabolismo , Riñón/metabolismo , Sirtuina 1/genética , Acetilación , Anciano , Animales , Apoptosis , Western Blotting , Estudios de Casos y Controles , Células Cultivadas , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Fibrosis , Proteína Forkhead Box O3 , Regulación de la Expresión Génica/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/metabolismo , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Técnicas In Vitro , Riñón/patología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Estrés Oxidativo , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Leptina/genética , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
13.
Transplantation ; 101(4): 671-674, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28323771

RESUMEN

Selected human immunodeficiency virus (HIV)-infected patients with end organ failure can safely receive an organ transplant from an HIV uninfected donor. Recent demonstration of the short term safety of organ transplantation between HIV-infected persons prompted a change in US American law to allow such transplantations. Prompted by the recent completion of the first organ transplantation between HIV-infected persons in Canada, we review Canadian law regarding the use of organs from HIV-infected donors, estimate the number of potential HIV-infected donors in Canada, and critically review considerations related to advancing organ transplantation from HIV-infected donors in Canada. Existing legislation allows organ transplantation from an HIV-infected donor under exceptional medical circumstances and therefore no change in legislation is required to increase utilization of organs from HIV-infected donors for transplantation in Canada. Among 335,793 hospital deaths between 2005 and 2009 in Canadian provinces excluding Quebec, 39 potential HIV-infected donors were identified. The actual number of HIV potential donors is estimated to be approximately 60% lower (3-5 potential donor per year), if the absence of viremia is required for transplantation. Although offering all Canadians the opportunity to donate organs is a laudable goal, further research to understand the need for HIV-positive donors and the willingness of HIV-positive recipients to accept organs from HIV-positive donors is needed to inform future policy regarding organ donation from HIV-infected persons in Canada.


Asunto(s)
Selección de Donante , Infecciones por VIH/epidemiología , Trasplante de Órganos/métodos , Donantes de Tejidos , Canadá/epidemiología , Selección de Donante/legislación & jurisprudencia , Infecciones por VIH/diagnóstico , Política de Salud , Humanos , Trasplante de Órganos/efectos adversos , Trasplante de Órganos/legislación & jurisprudencia , Seguridad del Paciente , Medición de Riesgo , Factores de Riesgo , Donantes de Tejidos/legislación & jurisprudencia
14.
J Immunol ; 198(2): 852-861, 2017 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-27940660

RESUMEN

Ubiquitination was recently identified as a central process in the pathogenesis and development of numerous inflammatory diseases, such as obesity, atherosclerosis, and asthma. Treatment with proteasomal inhibitors led to severe side effects because ubiquitination is heavily involved in a plethora of cellular functions. Thus, new players regulating ubiquitination processes must be identified to improve therapies for inflammatory diseases. In addition to their role in adaptive immunity, endosomal MHC class II (MHCII) molecules were shown to modulate innate immune responses by fine tuning the TLR4 signaling pathway. However, the role of MHCII ubiquitination by membrane associated ring-CH-type finger 1 (MARCH1) E3 ubiquitin ligase in this process remains to be assessed. In this article, we demonstrate that MARCH1 is a key inhibitor of innate inflammation in response to bacterial endotoxins. The higher mortality of March1-/- mice challenged with a lethal dose of LPS was associated with significantly stronger systemic production of proinflammatory cytokines and splenic NK cell activation; however, we did not find evidence that MARCH1 modulates LPS or IL-10 signaling pathways. Instead, the mechanism by which MARCH1 protects against endotoxic shock rests on its capacity to promote the transition of monocytes from Ly6CHi to Ly6C+/- Moreover, in competitive bone marrow chimeras, March1-/- monocytes and polymorphonuclear neutrophils outcompeted wild-type cells with regard to bone marrow egress and homing to peripheral organs. We conclude that MARCH1 exerts MHCII-independent effects that regulate the innate arm of immunity. Thus, MARCH1 might represent a potential new target for emerging therapies based on ubiquitination reactions in inflammatory diseases.


Asunto(s)
Endotoxemia/inmunología , Inmunidad Innata/inmunología , Inflamación/inmunología , Monocitos/inmunología , Ubiquitina-Proteína Ligasas/inmunología , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Antígenos de Histocompatibilidad Clase II/inmunología , Lipopolisacáridos/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Ubiquitinación
15.
Sci Rep ; 6: 37391, 2016 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-27874077

RESUMEN

Pathological choroidal neovascularization (CNV) is the common cause of vision loss in patients with age-related macular degeneration (AMD). Macrophages possess potential angiogenic function in CNV. We have demonstrated that human T lymphocyte-derived microparticles (LMPs) exert a potent antiangiogenic effect in several pathological neovascularization models. In this study, we investigated the alteration of proangiogenic properties of macrophages by LMPs treatment in vitro and in vivo models. LMPs regulated the expression of several angiogenesis-related factors in macrophages and consequently stimulated their antiangiogenic effects evidenced by the suppression of the proliferation of human retinal endothelial cells in co-culture experiments. The involvement of CD36 receptor in LMPs uptake by macrophages was demonstrated by in vitro assays and by immunostaining of choroidal flat mounts. In addition, ex vivo experiments showed that CD36 mediates the antiangiogenic effect of LMPs in murine and human choroidal explants. Furthermore, intravitreal injection of LMPs in the mouse model of laser-induced CNV significantly suppressed CNV in CD36 dependent manner. The results of this study suggested an ability of LMPs to alter the gene expression pattern of angiogenesis-related factors in macrophages, which provide important information for a new therapeutic approach for efficiently interfering with both vascular and extravascular components of CNV.


Asunto(s)
Micropartículas Derivadas de Células/metabolismo , Neovascularización Coroidal/patología , Linfocitos/metabolismo , Macrófagos/metabolismo , Neovascularización Fisiológica , Animales , Biomarcadores/metabolismo , Antígenos CD36/metabolismo , Polaridad Celular , Proliferación Celular , Regulación de la Expresión Génica , Humanos , Rayos Láser , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células RAW 264.7
16.
J Leukoc Biol ; 100(5): 1135-1146, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27260955

RESUMEN

Mediators released by apoptotic renal resident cells play a crucial role in modification of the inflammatory microenvironment. We have demonstrated that milk fat globule epidermal growth factor 8 (MFG-E8) is released by apoptotic cells, which results in reduced proinflammatory cytokine production by macrophages. The present study was designed to study the role of MFG-E8 on the modulation of tissue damage and macrophage phenotype in a renal inflammatory model, unilateral ureteral obstruction (UUO). C57BL/6 WT or MFG-E8 KO mice underwent ureteral ligation for 3, 7, and 14 d to evaluate renal injury. MFG-E8 (30 µg/kg) or vehicle was also administered i.p. MFG-E8 administration reduced kidney damage and fibrosis compared with control, whereas its absence in MFG-E8 KO mice was associated with more severe disease. Moreover, MFG-E8 administration was associated with decreased inflammasome activation in the kidney. Furthermore, adoptive transfer of MFG-E8-stimulated macrophages reduced activation of inflammasome and tissue damage. In all cases, both the systemic administration of MFG-E8 and MFG-E8-treated macrophages promoted accumulation of anti-inflammatory CD206+ macrophages. We propose that the protective role of MFG-E8 is mediated through anti-inflammatory macrophage reprogramming which results in decreased inflammasome activation, preventing severe tissue damage. These data provide valuable insight for identification of MFG-E8 as a novel target in modulation of inflammatory diseases.


Asunto(s)
Antígenos de Superficie/inmunología , Inflamasomas/inmunología , Macrófagos/inmunología , Proteínas de la Leche/inmunología , Nefritis/inmunología , Animales , Antígenos de Superficie/genética , Antígenos de Superficie/uso terapéutico , Apoptosis , Microambiente Celular , Colágeno/análisis , Inmunoterapia Adoptiva , Inflamasomas/efectos de los fármacos , Riñón/química , Riñón/inmunología , Riñón/patología , Macrófagos/efectos de los fármacos , Macrófagos/trasplante , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de la Leche/genética , Proteínas de la Leche/uso terapéutico , Nefritis/etiología , Nefritis/patología , Nefritis/terapia , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Obstrucción Ureteral/complicaciones
17.
Sci Transl Med ; 7(318): 318ra200, 2015 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-26676607

RESUMEN

Autoantibodies to components of apoptotic cells, such as anti-perlecan antibodies, contribute to rejection in organ transplant recipients. However, mechanisms of immunization to apoptotic components remain largely uncharacterized. We used large-scale proteomics, with validation by electron microscopy and biochemical methods, to compare the protein profiles of apoptotic bodies and apoptotic exosome-like vesicles, smaller extracellular vesicles released by endothelial cells downstream of caspase-3 activation. We identified apoptotic exosome-like vesicles as a central trigger for production of anti-perlecan antibodies and acceleration of rejection. Unlike apoptotic bodies, apoptotic exosome-like vesicles triggered the production of anti-perlecan antibodies in naïve mice and enhanced anti-perlecan antibody production and allograft inflammation in mice transplanted with an MHC (major histocompatibility complex)-incompatible aortic graft. The 20S proteasome core was active within apoptotic exosome-like vesicles and controlled their immunogenic activity. Finally, we showed that proteasome activity in circulating exosome-like vesicles increased after vascular injury in mice. These findings open new avenues for predicting and controlling maladaptive humoral responses to apoptotic cell components that enhance the risk of rejection after transplantation.


Asunto(s)
Lesión Renal Aguda/enzimología , Aorta/trasplante , Apoptosis/inmunología , Autoanticuerpos/biosíntesis , Micropartículas Derivadas de Células/enzimología , Exosomas/enzimología , Rechazo de Injerto/enzimología , Isquemia/enzimología , Complejo de la Endopetidasa Proteasomal/metabolismo , Lesión Renal Aguda/inmunología , Lesión Renal Aguda/patología , Aloinjertos , Animales , Aorta/enzimología , Aorta/inmunología , Aorta/patología , Autoanticuerpos/inmunología , Biomarcadores/metabolismo , Micropartículas Derivadas de Células/inmunología , Micropartículas Derivadas de Células/patología , Células Cultivadas , Modelos Animales de Enfermedad , Exosomas/inmunología , Exosomas/patología , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Proteoglicanos de Heparán Sulfato/inmunología , Proteoglicanos de Heparán Sulfato/metabolismo , Células Endoteliales de la Vena Umbilical Humana/enzimología , Células Endoteliales de la Vena Umbilical Humana/inmunología , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Inmunidad Humoral , Isquemia/inmunología , Isquemia/patología , Túbulos Renales Proximales/enzimología , Túbulos Renales Proximales/inmunología , Túbulos Renales Proximales/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/inmunología , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/inmunología , Miocitos del Músculo Liso/patología , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Complejo de la Endopetidasa Proteasomal/inmunología , Proteómica/métodos , Ratas , Factores de Tiempo
18.
Mult Scler ; 20(13): 1783-7, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24534079

RESUMEN

Three women aged 34-47 years old, on high dose interferon beta-1a for relapsing-remitting multiple sclerosis, were hospitalized between 2009-2012 for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Patients sought medical attention for neurological symptoms including cephalalgia, blurred vision, confusion, focal deficits and seizures. All patients presented thrombocytopenia, hemolytic anemia and arterial hypertension. Despite plasma exchanges, corticosteroids and anti-CD20 treatments, all patients progressed towards severe renal insufficiency and one patient died of hemorrhagic shock. In this report we identify a rare but morbid complication of interferon beta-1a treatment associated with female gender, Caucasian background and low body mass index.


Asunto(s)
Adyuvantes Inmunológicos/efectos adversos , Síndrome Hemolítico-Urémico/inducido químicamente , Interferón beta/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Púrpura Trombocitopénica Trombótica/inducido químicamente , Adulto , Femenino , Humanos , Interferón beta-1a , Persona de Mediana Edad
19.
PLoS One ; 7(6): e38541, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22685580

RESUMEN

BTN3A2/BT3.2 butyrophilin mRNA expression by tumoral cells was previously identified as a prognostic factor in a small cohort of high grade serous epithelial ovarian cancer (HG-EOC). Here, we evaluated the prognostic value of BT3.2 at the protein level in specimen from 199 HG-EOC patients. As the only known role of butyrophilin proteins is in immune regulation, we evaluated the association between BT3.2 expression and intratumoral infiltration of immune cells by immunohistochemistry with specific antibodies against BT3.2, CD3, CD4, CD8, CD20, CD68 and CD206. Epithelial BT3.2 expression was significantly associated with longer overall survival and lower risk of disease progression (HR=0.651, p=0.006 and HR=0.642, p=0.002, respectively) and significantly associated with a higher density of infiltrating T cells, particularly CD4+ cells (0.272, p<0.001). We also observed a strong association between the relative density of CD206+ cells, as evaluated by the ratio of intratumoral CD206+/CD68+ expression, and risk of disease progression (HR=1.355 p=0.044, respectively). In conclusion, BT3.2 protein is a potential prognostic biomarker for the identification of HG-EOC patients with better outcome. In contrast, high CD206+/CD68+ expression is associated with high risk of disease progression. While the role of BT3.2 is still unknown, our result suggest that BT3.2 expression by epithelial cells may modulates the intratumoral infiltration of immune cells.


Asunto(s)
Linfocitos Infiltrantes de Tumor/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/metabolismo , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Linfocitos T/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Western Blotting , Butirofilinas , Línea Celular Tumoral , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica/estadística & datos numéricos , Estimación de Kaplan-Meier , Lectinas Tipo C/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Lectinas de Unión a Manosa/metabolismo , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/genética , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Isoformas de Proteínas/metabolismo , Receptores de Superficie Celular/metabolismo , Linfocitos T/patología , Análisis de Matrices Tisulares/estadística & datos numéricos , Transfección
20.
PLoS One ; 7(4): e36368, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22558449

RESUMEN

Apoptotic endothelial cells are an important component of the "response to injury" process. Several atherosclerosis risk factors such as hyperglycemia and oxidized low-density lipoproteins, and immune injuries, such as antibodies and complement, induce endothelial cell apoptosis. While endothelial cell apoptosis is known to affect neighboring vascular wall cell biology, its consequences on macrophage reprogramming are ill defined. In this study, we report that apoptosis of human and mouse endothelial cells triggers the release of milk fat globule-epidermal growth factor 8 (MFG-E8) and reprograms macrophages into an anti-inflammatory cells. We demonstrated that MFG-E8 is released by apoptotic endothelial cells in a caspase-3-dependent manner. When macrophages were exposed to conditioned media from serum-starved apoptotic endothelial cells, they adopt a high anti-inflammatory, low pro-inflammatory cytokine/chemokine secreting phenotype that is lost if MFG-E8 is absent from the media. Macrophage treatment with recombinant MFG-E8 recapitulates the effect of conditioned media. Finally, we showed that MFG-E8-mediated reprogramming of macrophages occurs through increased phosphorylation of signal transducer and activator of transcription-3 (STAT-3). Taken together, our study suggests a key role of MFG-E8 release from apoptotic endothelial cells in macrophage reprogramming and demonstrates the importance of the apoptotic microenvironment in anti-inflammatory macrophage responses.


Asunto(s)
Apoptosis , Células Endoteliales/citología , Células Endoteliales/metabolismo , Macrófagos/citología , Macrófagos/inmunología , Proteínas de la Leche/metabolismo , Animales , Antígenos de Superficie/biosíntesis , Antígenos de Superficie/metabolismo , Antígenos de Superficie/farmacología , Caspasa 3/metabolismo , Medios de Cultivo Condicionados/metabolismo , Activación Enzimática/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamación/inmunología , Macrófagos/efectos de los fármacos , Ratones , Proteínas de la Leche/biosíntesis , Proteínas de la Leche/farmacología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos
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