RESUMO
There is a growing body of research on the neural control of immunity and inflammation. However, it is not known whether the nervous system can regulate the production of inflammatory myeloid cells from hematopoietic progenitor cells in disease conditions. Myeloid cell numbers in diabetic patients were strongly correlated with plasma concentrations of norepinephrine, suggesting the role of sympathetic neuronal activation in myeloid cell production. The spleens of diabetic patients and mice contained higher numbers of tyrosine hydroxylase (TH)-expressing leukocytes that produced catecholamines. Granulocyte macrophage progenitors (GMPs) expressed the ß2 adrenergic receptor, a target of catecholamines. Ablation of splenic sympathetic neuronal signaling using surgical, chemical, and genetic approaches diminished GMP proliferation and myeloid cell development. Finally, mice lacking TH-producing leukocytes had reduced GMP proliferation, resulting in diminished myelopoiesis. Taken together, our study demonstrates that catecholamines produced by leukocytes and sympathetic nerve termini promote GMP proliferation and myeloid cell development.
Assuntos
Diabetes Mellitus/fisiopatologia , Células Progenitoras de Granulócitos e Macrófagos/citologia , Células Progenitoras de Granulócitos e Macrófagos/metabolismo , Mielopoese , Neuroimunomodulação , Sistema Nervoso Simpático/metabolismo , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus/sangue , Modelos Animais de Doenças , Feminino , Humanos , Leucócitos/enzimologia , Leucócitos/metabolismo , Masculino , Camundongos , Células Mieloides/citologia , Mielopoese/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Norepinefrina/sangue , Transdução de Sinais/efeitos dos fármacos , Baço/citologia , Baço/inervação , Baço/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Insulin resistance is a compromised response to insulin in target tissues such as liver. Emerging evidence shows that vascular endothelial cells (ECs) are critical in mediating glucose metabolism. However, how liver ECs can regulate inflammation in the setting of insulin resistance is still unknown. Using genome-wide transcriptome analysis of ECs isolated from diabetic mice, we found enrichment of the genes involved in epidermal growth factor receptor (Egfr) signaling. In line with this, hepatic sinusoidal ECs in diabetic mice had elevated levels of Egfr expression. Interestingly, we found an increased number of hepatic myeloid cells, especially macrophages, and systemic glucose intolerance in Cdh5Cre/+Egfrfl/fl mice lacking Egfr in ECs compared with littermate control mice with type II diabetes. Egfr deficiency upregulated the expression of MCP-1 in hepatic sinusoidal ECs. This resulted in augmented monocyte recruitment and macrophage differentiation in Cdh5Cre/+Egfrfl/fl mice compared with littermate control mice as determined by a mouse model of parabiosis. Finally, MCP-1 neutralization and hepatic macrophage depletion in Cdh5Cre/+Egfrfl/fl mice resulted in a reduced number of hepatic macrophages and ameliorated glucose intolerance compared with the control groups. Collectively, these results demonstrate a protective endothelial Egfr signaling in reducing monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetic mice.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Resistência à Insulina , Camundongos , Animais , Monócitos/metabolismo , Intolerância à Glucose/metabolismo , Células Endoteliais/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fígado/metabolismo , Inflamação/metabolismo , Receptores ErbB/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Visceral adipose tissue (VAT) is a metabolic organ known to regulate fat mass, and glucose and nutrient homeostasis. VAT is an active endocrine gland that synthesizes and secretes numerous bioactive mediators called 'adipocytokines/adipokines' into systemic circulation. These adipocytokines act on organs of metabolic importance like the liver and skeletal muscle. Multiple preclinical and in vitro studies showed strong evidence of the roles of adipocytokines in the regulation of metabolic disorders like diabetes, obesity and insulin resistance. Adipocytokines, such as adiponectin and omentin, are anti-inflammatory and have been shown to prevent atherogenesis by increasing nitric oxide (NO) production by the endothelium, suppressing endothelium-derived inflammation and decreasing foam cell formation. By inhibiting differentiation of vascular smooth muscle cells (VSMC) into osteoblasts, adiponectin and omentin prevent vascular calcification. On the other hand, adipocytokines like leptin and resistin induce inflammation and endothelial dysfunction that leads to vasoconstriction. By promoting VSMC migration and proliferation, extracellular matrix degradation and inflammatory polarization of macrophages, leptin and resistin increase the risk of atherosclerotic plaque vulnerability and rupture. Additionally, the plasma concentrations of these adipocytokines alter in ageing, rendering older humans vulnerable to cardiovascular disease. The disturbances in the normal physiological concentrations of these adipocytokines secreted by VAT under pathological conditions impede the normal functions of various organs and affect cardiovascular health. These adipokines could be used for both diagnostic and therapeutic purposes in cardiovascular disease.
Assuntos
Doenças Cardiovasculares , Leptina , Humanos , Resistina/metabolismo , Adiponectina/metabolismo , Doenças Cardiovasculares/metabolismo , Gordura Intra-Abdominal/metabolismo , Adipocinas/metabolismo , Inflamação/metabolismo , Tecido Adiposo/metabolismoRESUMO
RATIONALE: Unproven theories abound regarding the long-range uptake and endocrine activity of extracellular blood-borne microRNAs into tissue. In pulmonary hypertension (PH), microRNA-210 (miR-210) in pulmonary endothelial cells promotes disease, but its activity as an extracellular molecule is incompletely defined. OBJECTIVE: We investigated whether chronic and endogenous endocrine delivery of extracellular miR-210 to pulmonary vascular endothelial cells promotes PH. METHODS AND RESULTS: Using miR-210 replete (wild-type [WT]) and knockout mice, we tracked blood-borne miR-210 using bone marrow transplantation and parabiosis (conjoining of circulatory systems). With bone marrow transplantation, circulating miR-210 was derived predominantly from bone marrow. Via parabiosis during chronic hypoxia to induce miR-210 production and PH, miR-210 was undetectable in knockout-knockout mice pairs. However, in plasma and lung endothelium, but not smooth muscle or adventitia, miR-210 was observed in knockout mice of WT-knockout pairs. This was accompanied by downregulation of miR-210 targets ISCU (iron-sulfur assembly proteins)1/2 and COX10 (cytochrome c oxidase assembly protein-10), indicating endothelial import of functional miR-210. Via hemodynamic and histological indices, knockout-knockout pairs were protected from PH, whereas knockout mice in WT-knockout pairs developed PH. In particular, pulmonary vascular engraftment of miR-210-positive interstitial lung macrophages was observed in knockout mice of WT-knockout pairs. To address whether engrafted miR-210-positive myeloid or lymphoid cells contribute to paracrine miR-210 delivery, we studied miR-210 knockout mice parabiosed with miR-210 WT; Cx3cr1 knockout mice (deficient in myeloid recruitment) or miR-210 WT; Rag1 knockout mice (deficient in lymphocytes). In both pairs, miR-210 knockout mice still displayed miR-210 delivery and PH, thus demonstrating a pathogenic endocrine delivery of extracellular miR-210. CONCLUSIONS: Endogenous blood-borne transport of miR-210 into pulmonary vascular endothelial cells promotes PH, offering fundamental insight into the systemic physiology of microRNA activity. These results also describe a platform for RNA-mediated crosstalk in PH, providing an impetus for developing blood-based miR-210 technologies for diagnosis and therapy in this disease.
Assuntos
Endotélio Vascular/metabolismo , Hipertensão Pulmonar/metabolismo , Pulmão/irrigação sanguínea , MicroRNAs/metabolismo , Animais , Transplante de Medula Óssea , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/sangue , MicroRNAs/genética , Parabiose , Transdução de SinaisRESUMO
Pulmonary inflammation, which is characterized by the presence of perivascular macrophages, has been proposed as a key pathogenic driver of pulmonary hypertension (PH), a vascular disease with increasing global significance. However, the mechanisms of expansion of lung macrophages and the role of blood-borne monocytes in PH are poorly understood. Using multicolor flow cytometric analysis of blood in mouse and rat models of PH and patients with PH, an increase in blood monocytes was observed. In parallel, lung tissue displayed increased chemokine transcript expression, including those responsible for monocyte recruitment, such as Ccl2 and Cx3cl1, accompanied by an expansion of interstitial lung macrophages. These data indicate that blood monocytes are recruited to lung perivascular spaces and differentiate into inflammatory macrophages. Correspondingly, parabiosis between congenically different hypoxic mice demonstrated that most interstitial macrophages originated from blood monocytes. To define the actions of these cells in PH in vivo, we reduced blood monocyte numbers via genetic deficiency of cx3cr1 or ccr2 in chronically hypoxic male mice and by pharmacologic inhibition of Cx3cl1 in monocrotaline-exposed rats. Both models exhibited decreased inflammatory blood monocytes, as well as interstitial macrophages, leading to a substantial decrease in arteriolar remodeling but with a less robust hemodynamic effect. This study defines a direct mechanism by which interstitial macrophages expand in PH. It also demonstrates a pathway for pulmonary vascular remodeling in PH that depends upon interstitial macrophage-dependent inflammation yet is dissociated, at least in part, from hemodynamic consequences, thus offering guidance on future anti-inflammatory therapeutic strategies in this disease.
Assuntos
Hipertensão Pulmonar/patologia , Macrófagos Alveolares/patologia , Monócitos/patologia , Pneumonia/patologia , Animais , Quimiocina CCL2/metabolismo , Humanos , Hipertensão Pulmonar/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Pneumonia/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores CCR2/metabolismoRESUMO
Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; "cross-dressing") of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a "split tolerance" status in mAAQ+ mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC-specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1-dependent anergy in mAAQ+ hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.
Assuntos
Quimerismo , Células Dendríticas/imunologia , Vesículas Extracelulares/imunologia , Tolerância Imunológica , Transferência Adotiva , Animais , Antígeno B7-2/biossíntese , Antígeno B7-2/imunologia , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Transfusão Feto-Materna/imunologia , Antígenos H-2/genética , Antígenos H-2/imunologia , Antígeno de Histocompatibilidade H-2D/genética , Antígeno de Histocompatibilidade H-2D/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Isoantígenos/imunologia , Masculino , Troca Materno-Fetal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Imunológicos , Gravidez , Especificidade do Receptor de Antígeno de Linfócitos TRESUMO
Splenic hematopoiesis is crucial to the pathogenesis of diseases including myocardial infarction and atherosclerosis. The spleen acts as a reservoir of myeloid cells, which are quickly expelled out in response to acute inflammation. In contrast to the well-defined bone marrow hematopoiesis, the cellular and molecular components sustaining splenic hematopoiesis are poorly understood. Surprisingly, we found that, unlike quiescent bone marrow hematopoietic stem cells (HSC), most of splenic HSC are in the G1 phase in C57BL/6 mice. Moreover, splenic HSC were enriched for genes involved in G0-G1 transition and expressed lower levels of genes responsible for G1-S transition. These data indicate that, at steady state, splenic HSC are pre-activated, which may expedite their cell cycle entry in emergency conditions. Consistently, in the acute phase of septic shock induced by LPS injection, splenic HSC entered the S-G2-M phase, whereas bone marrow HSC did not. Mobilization and transplantation experiments displayed that bone marrow HSC, once in the spleen, acquired cell cycle status similar to splenic HSC, strongly suggesting that the splenic microenvironment plays an important role in HSC pre-activation. In addition, we found that myeloid translocation gene 16 (Mtg16) deficiency in C57BL/6 mice resulted in significantly increased S-G2-M entry of splenic but not bone marrow HSC, suggesting that Mtg16 is an intrinsic negative regulator of G1-S transition in splenic HSC. Altogether, this study demonstrates that compared to bone marrow, splenic HSC are in a pre-activated state, which is driven by extracellular signals provided by splenic microenvironment and HSC intrinsic factor Mtg16.
RESUMO
Myeloid cells, including monocytes and macrophages participate in steady state immune homeostasis and help mount the adaptive immune response during infection. The function and production of these cells in sterile inflammation, such as pulmonary hypertension (PH), is understudied. Emerging data indicate that pulmonary inflammation mediated by lung perivascular macrophages is a key pathogenic driver of pulmonary remodeling leading to increased right ventricular systolic pressure (RVSP). However, the origin of these macrophages in pulmonary inflammation is unknown. Inflammatory monocytes, the precursors of pathogenic macrophages, are derived from hematopoietic stem and progenitor cells (HSPC) in the bone marrow and spleen during acute and chronic inflammation. Understanding the role of these organs in monocytopoiesis, and the mechanisms of HSPC proliferation and differentiation in PH are important to discover therapeutic targets curbing inflammation. This review will summarize the current limited knowledge of the origin of lung macrophage subsets and over-production of inflammatory monocytes in PH.
Assuntos
Células-Tronco Hematopoéticas/fisiologia , Hipertensão Pulmonar/imunologia , Macrófagos Alveolares/imunologia , Macrófagos/imunologia , Pneumonia/imunologia , Animais , Pressão Sanguínea , Diferenciação Celular , Proliferação de Células , Humanos , Hipertensão Pulmonar/fisiopatologia , Macrófagos/fisiologia , Macrófagos Alveolares/fisiologia , Camundongos , Monócitos/imunologia , Monócitos/fisiologia , Pneumonia/fisiopatologiaRESUMO
The elimination of hepatitis C virus (HCV) in > 50% of chronically infected patients by treatment with IFN-α suggests that plasmacytoid dendritic cells (pDCs), major producers of IFN-α, play an important role in the control of HCV infection. However, despite large amounts of Toll-like receptor 7-mediated IFN-α, produced by pDCs exposed to HCV-infected hepatocytes, HCV still replicates in infected liver. Here we show that HCV envelope glycoprotein E2 is a novel ligand of pDC C-type lectin immunoreceptors (CLRs), blood DC antigen 2 (BDCA-2) and DC-immunoreceptor (DCIR). HCV particles inhibit, via binding of E2 glycoprotein to CLRs, production of IFN-α and IFN-λ in pDCs exposed to HCV-infected hepatocytes, and induce in pDCs a rapid phosphorylation of Akt and Erk1/2, in a manner similar to the crosslinking of BDCA-2 or DCIR. Blocking of BDCA-2 and DCIR with Fab fragments of monoclonal antibodies preserves the capacity of pDCs to produce type I and III IFNs in the presence of HCV particles. Thus, negative interference of CLR signaling triggered by cell-free HCV particles with Toll-like receptor signaling triggered by cell-associated HCV results in the inhibition of the principal pDC function, production of IFN.
Assuntos
Células Dendríticas/imunologia , Interferons/imunologia , Lectinas Tipo C/imunologia , Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/imunologia , Proteínas do Envelope Viral/imunologia , Animais , Células COS , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Células Cultivadas , Chlorocebus aethiops , Células Dendríticas/metabolismo , Células Dendríticas/virologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo , Hepacivirus/imunologia , Hepacivirus/metabolismo , Hepacivirus/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interferons/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ligantes , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo , Proteínas do Envelope Viral/metabolismoRESUMO
SARGASSUM SEAWEED AS SAULTS THE FRENCH WEST INDIES. Since 2011, Martinique and the islands of Guadeloupe have been affected by repeated groundings, culminating in an exceptional wave in 2018. While the sargassum ( Sargassum natans and S. fluitans ) involved in these phenomena are neither toxic nor urticating, indirect toxicity linked to the presence of microorganisms and heavy metals (arsenic, mercury, etc.) in sargassum clusters has been described. Similarly, after a 24 to 48 hours stay on the shore, sargassum algae enter a putrefaction cycle responsible to produce hydrogen sulfide (H2S) and ammonia (NH3). The acute toxicity of these gases is well known. However, very few data are available on the clinical effects of prolonged exposure to low doses of H2S and NH3. Our team has recently described the syndromic features of chronic exposure, supposing for deleterious effects on the cardiovascular, respiratory and neurological systems.
ALGUES SARGASSES À L'ASSAUT DES ANTILLES. Depuis 2011, la Martinique et les îles de la Guadeloupe sont touchées par des échouements à répétition d'algues sargasses qui ont culminé avec une vague exceptionnelle en 2018. Si les sargasses (Sargassum natans et S. fluitans) impliquées dans ces phénomènes ne sont ni toxiques ni urticantes, une toxicité indirecte liée à la présence de micro-organismes et de métaux lourds (arsenic, mercure ) dans les amas de sargasses est décrite. De même, après un séjour de vingt-quatre à quarante-huit heures sur le littoral, les algues sargasses entrent dans un cycle de putréfaction responsable de la production d'hydrogène sulfuré (H2S) et d'ammoniac (NH3). La toxicité aiguë de ces gaz est bien connue. Il existe en revanche très peu de données disponibles sur les effets cliniques d'une exposition prolongée à de faibles doses d'H2S ou NH3. Notre équipe a récemment décrit le tableau syndromique de l'exposition chronique et suppose des effets délétères sur le système cardiovasculaire, respiratoire et neurologique.
Assuntos
Sargassum , Alga Marinha , Humanos , Sulfeto de Hidrogênio/intoxicação , Sulfeto de Hidrogênio/toxicidade , Guadalupe/epidemiologia , Martinica/epidemiologia , Amônia/toxicidade , Índias Ocidentais/epidemiologia , Exposição Ambiental/efeitos adversosRESUMO
BACKGROUND: Sargassum invasion of Caribbean and American shorelines is a recurring environmental hazard. Potential health effects of long-term chronic exposure to sargassum gaseous emissions, notably hydrogen sulfide (H2S), are overlooked. H2S plays an important role in neurotransmission and is involved in generating and transmitting respiratory rhythm. Central sleep apnea (CSA) has been attributed to the depression of respiratory centers. OBJECTIVE: Evaluate the effects of exposure to sargassum-H2S on CSA. METHODS: This study, set in the Caribbean, describes the clinical and polysomnographic characteristics of individuals living and/or working in areas impacted by sargassum strandings, in comparison with non-exposed subjects. Environmental exposure was estimated by the closest ground H2S sensor. Multivariate linear regression was applied to analyze CSA changes according to cumulative H2S exposure over time. Effects of air pollution and other sargassum toxic compounds (NH3) on CSA were also controlled. RESULTS: Among the 685 study patients, 27 % were living and/or working in sargassum impacted areas. Compared with non-exposed patients, exposed ones had similar sleep apnea syndrome risk factors, but had increased levels of CSA events (expressed as absolute number or % of total sleep apnea). Multivariate regression retained only male gender and mean H2S concentration over a 6-month exposure period as independent predictors of an increase in CSA events. A minimal exposure length of 1 month generated a significant rise in CSA events, with the latter increasing proportionally with a cumulative increase in H2S concentration over time. CONCLUSION: This pioneer work highlights a potential effect of sargassum-H2S on the central nervous system, notably on the modulation of the activity of the brain's respiratory control center. These observations, jointly with previous studies from our group, constitute a body of evidence strongly supporting a deleterious effect of sargassum-H2S on the health of individuals chronically exposed to low to moderate concentration levels over time.
Assuntos
Sulfeto de Hidrogênio , Sargassum , Síndromes da Apneia do Sono , Apneia do Sono Tipo Central , Humanos , Masculino , Apneia do Sono Tipo Central/complicações , Sulfeto de Hidrogênio/toxicidade , Síndromes da Apneia do Sono/etiologia , Região do CaribeRESUMO
Bothrofav, a monospecific antivenom, was introduced in June 1991 and has shown excellent effectiveness against life-threatening and thrombotic complications of Bothrops lanceolatus envenoming. Because of the reoccurrence of cerebral stroke events despite the timely administration of antivenom, new batches of Bothrofav were produced and introduced into clinical use in January 2011. This study's aim was to evaluate the effectiveness of Bothrofav generations at treating B. lanceolatus envenoming. During the first period of the study (2000-2010), 107 patients were treated with vials of antivenom produced in June 1991, while 282 envenomed patients were treated with vials of antivenom produced in January 2011 in the second study period (2011-2023). Despite timely antivenom administration, thrombotic complications reoccurred after an interval free of thrombotic events, and a timeframe analysis suggested that the clinical efficacy of Bothrofav declined after it reached its 10-year shelf-life. In of the case of an antivenom shortage due to the absence of regular batch production, no adverse effects were identified before the antivenom reached its 10-year shelf-life, which is beyond the accepted shelf-life for a liquid-formulation antivenom. While our study does not support the use of expired antivenom for potent, life-threatening B. lanceolatus envenoming, it can be a scientific message to public entities proving the necessity of new antivenom production for B. lanceolatus envenoming.
Assuntos
Antivenenos , Bothrops , Serpentes Peçonhentas , Humanos , Animais , Martinica , Resultado do TratamentoRESUMO
There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
Assuntos
Aterosclerose , DNA Mitocondrial , Inflamação , Macrófagos , Proteínas de Membrana , Placa Aterosclerótica , Molécula 1 de Adesão de Célula Vascular , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Animais , Molécula 1 de Adesão de Célula Vascular/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Macrófagos/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética , Camundongos , Placa Aterosclerótica/patologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Camundongos Knockout para ApoE , Transdução de Sinais , Feminino , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismoRESUMO
Plasmacytoid dendritic cells (pDCs) respond to viral infection by production of alpha interferon (IFN-α), proinflammatory cytokines, and cell differentiation. The elimination of hepatitis C virus (HCV) in more than 50% of chronically infected patients by treatment with IFN-α suggests that pDCs can play an important role in the control of HCV infection. pDCs exposed to HCV-infected hepatoma cells, in contrast to cell-free HCV virions, produce large amounts of IFN-α. To further investigate the molecular mechanism of HCV sensing, we studied whether exposure of pDCs to HCV-infected hepatoma cells activates, in parallel to interferon regulatory factor 7 (IRF7)-mediated production of IFN-α, nuclear factor kappa B (NF-κB)-dependent pDC responses, such as expression of the differentiation markers CD40, CCR7, CD86, and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and secretion of the proinflammatory cytokines TNF-α and interleukin 6 (IL-6). We demonstrate that exposure of pDCs to HCV-infected hepatoma cells surprisingly did not induce phosphorylation of NF-κB or cell surface expression of CD40, CCR7, CD86, or TRAIL or secretion of TNF-α and IL-6. In contrast, CpG-A and CpG-B induced production of TNF-α and IL-6 in pDCs exposed to the HCV-infected hepatoma cells, showing that cell-associated virus did not actively inhibit Toll-like receptor (TLR)-mediated NF-κB phosphorylation. Our results suggest that cell-associated HCV signals in pDCs via an endocytosis-dependent mechanism and IRF7 but not via the NF-κB pathway. In spite of IFN-α induction, cell-associated HCV does not induce a full functional response of pDCs. These findings contribute to the understanding of evasion of immune responses by HCV.
Assuntos
Células Dendríticas/imunologia , Células Dendríticas/virologia , Hepacivirus/fisiologia , Hepatite C/imunologia , NF-kappa B/imunologia , Transdução de Sinais , Linhagem Celular Tumoral , Células Cultivadas , Hepacivirus/genética , Hepatite C/genética , Hepatite C/virologia , Humanos , Interferon-alfa/genética , Interferon-alfa/imunologia , NF-kappa B/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Snakebite envenomation is a relevant medical hazard in French Guiana and Martinique, two French territories in the Americas. All snakebite envenomations in Martinique are inflicted by the endemic viperid species Bothrops lanceolatus, whereas Bothrops atrox is responsible for the majority of snakebites in French Guiana, although other venomous snake species also occur in this South American territory. This review summarizes some of the key aspects of the natural history of these species, as well as of their venom composition, the main clinical manifestations of envenomations, and their treatment by antivenoms. B. atrox venom induces the typical set of clinical manifestations characteristic of Bothrops sp. venoms, i.e., local tissue damage and systemic alterations associated with coagulopathies, hemorrhage, hemodynamic alterations, and acute kidney injury. In the case of B. lanceolatus venom, in addition to some typical features of bothropic envenomation, a unique and severe thrombotic effect occurs in some patients. The pathogenesis of this effect remains unknown but may be related to the action of venom components and inflammatory mediators on endothelial cells in the vasculature. A monospecific antivenom has been successfully used in Martinique to treat envenomations by B. lanceolatus. In the case of French Guiana, a polyvalent antivenom has been used for some years, but it is necessary to assess the preclinical and clinical efficacy against viperid venoms in this country of other antivenoms manufactured in the Americas.
Assuntos
Bothrops , Venenos de Crotalídeos , Mordeduras de Serpentes , Animais , Mordeduras de Serpentes/tratamento farmacológico , Mordeduras de Serpentes/epidemiologia , Antivenenos/uso terapêutico , Guiana , Martinica , Células Endoteliais , ImunoterapiaRESUMO
Rubigine® is an anti-rust stain remover containing fluorides which is believed to have been the cause of many deaths in Martinique. However, after the modification of its composition in 2006, serious poisoning from old formulas containing fluorides persisted. Our main objective was to determine the clinical characteristics and prognostic factors of these intoxications. Methods: Any patient admitted to the Martinique University Hospital for acute Rubigine® poisoning was included from 1 January 2000 to 31 December 2016. Usual demographic and clinical data were collected and comparisons between surviving and deceased patients made using a univariate analysis and logistic regression. Results: Fifty-five patients were included (mean age: 43 years; sex ratio M/F: 1.1), and the main clinical characteristics were: changes in electrocardiogram (ECG) (80%), digestive system disorders (75%), and neurological disorders (12%). The main features linked to death were the presence of hydrofluoric acid (p < 0.0001), age over 55 years (p = 0.01), hypocalcemia after the initial intravenous calcium supplementation (p = 0.0003), diarrhea (p < 0.0001), hypersialorrhea (p < 0.0001), myocardial excitability (p < 0.0001), and state of shock (p < 0.0001). Three patients required circulatory support by venous-arterial ECMO. Mortality was 10.9%. Conclusions: Rubigine® poisoning is responsible for significant morbidity and mortality. Fortunately, its incidence as well as mortality has sharply decreased in Martinique thanks to the measures taken by the French state. This retrospective work nevertheless shows that acute intoxication by the old formula of Rubigine® remains the main factor of poor prognosis.