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1.
Nat Rev Immunol ; 21(10): 625, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34580463
2.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34437091

RESUMO

The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)-binding protein (LBP). HDL3, but not HDL2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL.


Assuntos
Intestino Delgado/metabolismo , Lipoproteínas HDL3/metabolismo , Hepatopatias/prevenção & controle , Fígado/metabolismo , Veia Porta/metabolismo , Proteínas de Fase Aguda/metabolismo , Adulto , Animais , Proteínas de Transporte/metabolismo , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Enterócitos/metabolismo , Humanos , Intestino Delgado/cirurgia , Macrófagos do Fígado/imunologia , Macrófagos do Fígado/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/metabolismo , Lipoproteínas HDL3/sangue , Fígado/patologia , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Hepatopatias/patologia , Receptores X do Fígado/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
3.
Nat Commun ; 12(1): 3350, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099721

RESUMO

Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.


Assuntos
Antígenos CD36/genética , Antígenos CD36/metabolismo , Células Endoteliais/metabolismo , Resistência à Insulina/fisiologia , Obesidade Abdominal/metabolismo , Animais , Antígenos CD , Caderinas , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose/metabolismo , Inflamação , Vasos Linfáticos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fosforilação , Transcriptoma , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Cell Metab ; 33(7): 1449-1465.e6, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34038712

RESUMO

The lymphatic vasculature plays important roles in the physiology of the organs in which it resides, though a clear mechanistic understanding of how this crosstalk is mediated is lacking. Here, we performed single-cell transcriptional profiling of human and mouse adipose tissue and found that lymphatic endothelial cells highly express neurotensin (NTS/Nts). Nts expression is reduced by cold and norepinephrine in an α-adrenergic-dependent manner, suggesting a role in adipose thermogenesis. Indeed, NTS treatment of brown adipose tissue explants reduced expression of thermogenic genes. Furthermore, adenoviral-mediated overexpression and knockdown or knockout of NTS in vivo reduced and enhanced cold tolerance, respectively, an effect that is mediated by NTSR2 and ERK signaling. Inhibition of NTSR2 promoted energy expenditure and improved metabolic function in obese mice. These data establish a link between adipose tissue lymphatics and adipocytes with potential therapeutic implications.

5.
JAMA Netw Open ; 4(5): e2111398, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34032853

RESUMO

Importance: Male sex is a risk factor for developing severe COVID-19 illness. It is not known whether sex hormones contribute to this predisposition. Objective: To investigate the association of concentrations of serum testosterone, estradiol, and insulinlike growth factor 1 (IGF-1, concentrations of which are regulated by sex hormone signaling) with COVID-19 severity. Design, Setting, and Participants: This prospective cohort study was conducted using serum samples collected from consecutive patients who presented from March through May 2020 to the Barnes Jewish Hospital in St Louis, Missouri, with COVID-19 (diagnosed using nasopharyngeal swabs). Exposures: Testosterone, estradiol, and IGF-1 concentrations were measured at the time of presentation (ie, day 0) and at days 3, 7, 14, and 28 after admission (if the patient remained hospitalized). Main Outcomes and Measures: Baseline hormone concentrations were compared among patients who had severe COVID-19 vs those with milder COVID-19 illness. RNA sequencing was performed on circulating mononuclear cells to understand the mechanistic association of altered circulating hormone concentrations with cellular signaling pathways. Results: Among 152 patients (90 [59.2%] men; 62 [40.8%] women; mean [SD] age, 63 [16] years), 143 patients (94.1%) were hospitalized. Among 66 men with severe COVID-19, median [interquartile range] testosterone concentrations were lower at day 0 (53 [18 to 114] ng/dL vs 151 [95 to 217] ng/dL; P = .01) and day 3 (19 [6 to 68] ng/dL vs 111 [49 to 274] ng/dL; P = .006) compared with 24 men with milder disease. Testosterone concentrations were inversely associated with concentrations of interleukin 6 (ß = -0.43; 95% CI, -0.52 to -0.17; P < .001), C-reactive protein (ß = -0.38; 95% CI, -0.78 to -0.16; P = .004), interleukin 1 receptor antagonist (ß = -0.29; 95% CI, -0.64 to -0.06; P = .02), hepatocyte growth factor (ß = -0.46; 95% CI, -0.69 to -0.25; P < .001), and interferon γ-inducible protein 10 (ß = -0.32; 95% CI, -0.62 to -0.10; P = .007). Estradiol and IGF-1 concentrations were not associated with COVID-19 severity in men. Testosterone, estradiol, and IGF-1 concentrations were similar in women with and without severe COVID-19. Gene set enrichment analysis revealed upregulated hormone signaling pathways in CD14+CD16- (ie, classical) monocytes and CD14-CD16+ (ie, nonclassical) monocytes in male patients with COVID-19 who needed intensive care unit treatment vs those who did not. Conclusions and Relevance: In this single-center cohort study of patients with COVID-19, lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men. Hormone signaling pathways in monocytes did not parallel serum hormone concentrations, and further investigation is required to understand their pathophysiologic association with COVID-19.


Assuntos
COVID-19/sangue , Hospitalização , Inflamação/etiologia , Índice de Gravidade de Doença , Testosterona/sangue , Idoso , COVID-19/complicações , COVID-19/patologia , Estradiol/sangue , Feminino , Hormônios Esteroides Gonadais/sangue , Hospitais , Humanos , Inflamação/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Missouri , SARS-CoV-2 , Fatores Sexuais
6.
Am J Physiol Gastrointest Liver Physiol ; 320(5): G907-G918, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33729834

RESUMO

Intestinal failure-associated liver disease is a major morbidity associated with short bowel syndrome. We sought to determine if the obesity-resistant mouse strain (129S1/SvImJ) conferred protection from liver injury after small bowel resection (SBR). Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6J and 129S1/SvImJ mice underwent a 50% proximal SBR or sham operation. At postoperative week 10, hepatic steatosis, fibrosis, and cholestasis were assessed. Hepatic and systemic inflammatory pathways were evaluated using oxidative markers and abundance of tissue macrophages. Potential mechanisms of endotoxin resistance were also explored. Serum lipid levels were elevated in all mouse lines. Hepatic triglyceride levels were no different between mouse strains, but there was an increased accumulation of free fatty acids in the C57BL/6J mice. Histological and serum markers of hepatic fibrosis, steatosis, and cholestasis were significantly elevated in resected C57BL/6J SBR mice as well as oxidative stress markers and macrophage recruitment in both the liver and visceral white fat in C57BL/6J mice compared with sham controls and the 129S1/SvImJ mouse line. Serum endotoxin levels were significantly elevated in C57BL/6J mice with significant elevation of hepatic TLR4 and reduction in PPARα expression levels. Despite high levels of serum lipids, 129S1/SvImJ mice did not develop liver inflammation, fibrosis, or cholestasis after SBR, unlike C57BL/6J mice. These data suggest that the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 contribute to the liver injury seen in C57BL/6J mice with short bowel syndrome.NEW & NOTEWORTHY Unlike C57BL/6 mice, the 129S1/SvImJ strain is resistant to liver inflammation and injury after small bowel resection. These disparate outcomes are likely due to the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 in C57BL/6 mice with short bowel syndrome.


Assuntos
Hepatopatias/etiologia , Fígado/metabolismo , Síndrome do Intestino Curto/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Biomarcadores/sangue , Procedimentos Cirúrgicos do Sistema Digestório , Modelos Animais de Doenças , Endotoxinas/sangue , Ácidos Graxos não Esterificados/metabolismo , Intestino Delgado/cirurgia , Lipídeos/sangue , Cirrose Hepática/metabolismo , Hepatopatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Triglicerídeos/metabolismo
7.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33688923

RESUMO

Gwendalyn Randolph shares her observations and ideas for how institutions can partner with women to support their careers in STEM.


Assuntos
Liderança , Pessoal de Laboratório Médico , Pesquisadores , Mulheres Trabalhadoras , Mobilidade Ocupacional , Feminino , Humanos , Masculino , Mães , Licença Parental , Fatores Sexuais , Assédio Sexual
8.
Trends Immunol ; 42(3): 180-182, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33563563

RESUMO

The nervous system plays important roles in homeostasis and inflammatory responses in tissues. However, the regulation of lymph nodes (LN) by nerves remains largely unknown. Huang et al. demonstrate that LNs are innervated by unique peptidergic nociceptors that signal to various endothelial, stromal, and immune cell types in LNs.


Assuntos
Imunidade , Linfonodos , Homeostase , Células Receptoras Sensoriais , Células Estromais
9.
J Exp Med ; 218(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33600554

RESUMO

Ralph M. Steinman's work on dendritic cells began in 1973 when he described and named the cells. Reminiscent of the late Justice Ginsburg's perspective that enduring change happens not suddenly but one step at a time, the paper (1973. J. Exp. Med.https://doi.org/10.1084/jem.137.5.1142) was notably the first step in many steps of important work that revealed the nature of dendritic cells.


Assuntos
Células Dendríticas/citologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Fagócitos/citologia , Fagócitos/metabolismo , Fagocitose
10.
Mol Pharm ; 18(3): 1386-1396, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33591187

RESUMO

Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo, we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64Cu radiolabeling showed extended blood circulation of 64Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE-/-) showed that the three 64Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE-/- mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.

11.
Gastroenterology ; 160(6): 2200-2201, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33484689
12.
Arterioscler Thromb Vasc Biol ; 41(2): 822-836, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33327748

RESUMO

OBJECTIVE: vMIP-II (viral macrophage inflammatory protein 2)/vCCL2 (viral chemotactic cytokine ligand 2) binds to multiple chemokine receptors, and vMIP-II-based positron emission tomography tracer (64Cu-DOTA-vMIP-II: vMIP-II tracer) accumulates at atherosclerotic lesions in mice. Given that it would be expected to react with multiple chemokine receptors on monocytes and macrophages, we wondered if its accumulation in atherosclerosis lesion-bearing mice might correlate with overall macrophage burden or, alternatively, the pace of monocyte recruitment. Approach and Results: We employed a mouse model of atherosclerosis regression involving adenoassociated virus 8 vector encoding murine Apoe (AAV-mApoE) treatment of Apoe-/- mice where the pace of monocyte recruitment slows before macrophage burden subsequently declines. Accumulation of 64Cu-DOTA-vMIP-II at Apoe-/- plaque sites was strong but declined with AAV-mApoE-induced decline in monocyte recruitment, before macrophage burden reduced. Monocyte depletion indicated that monocytes and macrophages themselves were not the only target of the 64Cu-DOTA-vMIP-II tracer. Using fluorescence-tagged vMIP-II tracer, competitive receptor blocking with CXCR4 antagonists, endothelial-specific Cre-mediated deletion of CXCR4, CXCR4-specific tracer 64Cu-DOTA-FC131, and CXCR4 staining during disease progression and regression, we show endothelial cell expression of CXCR4 is a key target of 64Cu-DOTA-vMIP-II imaging. Expression of CXCR4 was low in nonplaque areas but strongly detected on endothelium of progressing plaques, especially on proliferating endothelium, where vascular permeability was increased and monocyte recruitment was the strongest. CONCLUSIONS: Endothelial injury status of plaques is marked by CXCR4 expression and this injury correlates with the tendency of such plaques to recruit monocytes. Furthermore, our findings suggest positron emission tomography tracers that mark CXCR4 can be used translationally to monitor the state of plaque injury and monocyte recruitment.


Assuntos
Aorta Torácica/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Quimiocinas/administração & dosagem , Endotélio Vascular/diagnóstico por imagem , Imagem Molecular , Monócitos/metabolismo , Compostos Organometálicos/administração & dosagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Receptores CXCR4/metabolismo , Animais , Aorta Torácica/imunologia , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/metabolismo , Linhagem Celular , Quimiocinas/farmacocinética , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Injeções Intravenosas , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Monócitos/imunologia , Monócitos/patologia , Compostos Organometálicos/farmacocinética , Placa Aterosclerótica , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/farmacocinética , Receptores CXCR4/genética
13.
J Vis Exp ; (165)2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33283786

RESUMO

Lymphatic collecting vessels and lymph nodes are inevitably embedded in adipose tissue. The physiological significance of this observation remains still not elucidated. However, obesity is characterized by impaired lymphatic function and increased vessel permeability. Inversely, lymphatic dysfunction induces obesity in mice, suggesting a significant interplay between lymphatic vessels and the adipose tissue. Therefore, understanding factors leading to lymphatic dysfunction might open new therapeutic windows to prevent obesity and associated comorbidities. The first step in this process requires a precise and detailed visualization of the lymphatic network in healthy and inflamed adipose tissue. Here, we describe a rapid, inexpensive, and efficient method that allows to label and analyze lymphatic and blood vessels. This approach takes advantage of the skin-draining brachial lymph node localization within the subcutaneous adipose tissue. The lymphatic arborization of this tissue can be revealed by injecting fluorochrome-conjugated lectins subcutaneously. Moreover, the in vivo labeling approach provides a way to evaluate lymphatic vessel density and functions. Coupled to blood vessel, adipocyte and immune cell staining, the protocol allows for high-resolution mapping of the subcutaneous adipose tissue by 3D imaging.


Assuntos
Vasos Sanguíneos/patologia , Vasos Linfáticos/patologia , Obesidade/sangue , Obesidade/patologia , Animais , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Coloração e Rotulagem , Gordura Subcutânea/irrigação sanguínea
14.
Cell ; 183(2): 305-307, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33064986

RESUMO

How the colon microenvironment confronts a breach of its epithelial border remains incompletely understood. In this issue, the laboratories of Lennon-Duménil and Vignjevic reveal a novel role for macrophages in sustaining epithelial integrity in the face of fungal metabolites.


Assuntos
Colo , Macrófagos , Epitélio
15.
Development ; 147(23)2020 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-33060128

RESUMO

Lymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and vascular endothelial growth factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the first time that VEGF-C signaling is necessary for valve morphogenesis. We have also discovered that the transcriptional co-activators YAP and TAZ are required to maintain PROX1 expression in LVs and LVVs in response to VEGF-C signaling. Deletion of Yap and Taz in the lymphatic vasculature of mouse embryos did not affect the formation of LVs or LVVs, but resulted in the degeneration of these structures. Our results have identified VEGF-C, YAP and TAZ as a crucial molecular pathway in valve development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ciclo Celular/genética , Proteínas de Homeodomínio/genética , Linfangiogênese/genética , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Vasos Linfáticos/citologia , Vasos Linfáticos/metabolismo , Camundongos , Morfogênese/genética , Transdução de Sinais/genética , Válvulas Venosas/crescimento & desenvolvimento , Válvulas Venosas/metabolismo
16.
Nat Immunol ; 21(10): 1194-1204, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32895539

RESUMO

Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DCs) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage-tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aortic intima resident macrophages (MacAIR) that depend upon colony-stimulating factor 1 and are sustained by local proliferation. Although MacAIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaques is overtaken by recruited monocytes, which induce MacAIR-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.


Assuntos
Aorta/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Placa Aterosclerótica/imunologia , Túnica Íntima/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Movimento Celular , Proliferação de Células , Células Cultivadas , Colesterol/metabolismo , Progressão da Doença , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parabiose , Fagocitose
17.
Sci Rep ; 10(1): 14129, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839504

RESUMO

Cardiac myocytes have multiple cell autonomous mechanisms that facilitate stabilization and repair of damaged sarcolemmal membranes following myocardial injury. Dysferlin is a protein which facilitates membrane repair by promoting membrane resealing. Although prior studies have shown that dysferlin-deficient (Dysf-/-) mouse hearts have an impaired recovery from acute ischemia/reperfusion (I/R) injury ex vivo, the role of dysferlin in mediating the recovery from myocardial injury in vivo is unknown. Here we show that Dysf-/- mice develop adverse LV remodeling following I/R injury secondary to the collateral damage from sustained myocardial inflammation within the infarct zone. Backcrossing Dysf-/- mice with mice lacking signaling through the Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein (Tirap-/-), attenuated inflammation and abrogated adverse LV remodeling following I/R injury. Subsequent studies using Poloxamer 188 (P188), a membrane resealing reagent, demonstrated that P188 did not attenuate inflammation nor prevent adverse LV remodeling in Dysf-/- mice following I/R injury. Viewed together these studies reveal a previously unappreciated role for the importance of membrane sealing and the resolution of inflammation following myocardial injury.


Assuntos
Disferlina/genética , Glicoproteínas de Membrana/metabolismo , Isquemia Miocárdica/patologia , Receptores de Interleucina-1/metabolismo , Traumatismo por Reperfusão/patologia , Remodelação Ventricular/fisiologia , Animais , Cardiotônicos/farmacologia , Disferlina/deficiência , Inflamação/patologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , Fosfolipídeos/metabolismo , Poloxâmero/farmacologia , Receptores de Interleucina-1/genética , Sarcolema/fisiologia , Transdução de Sinais , Tensoativos/farmacologia
19.
Cell ; 182(2): 270-296, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32707093

RESUMO

Mammals have two specialized vascular circulatory systems: the blood vasculature and the lymphatic vasculature. The lymphatic vasculature is a unidirectional conduit that returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays major roles in immune cell trafficking and lipid absorption. As we discuss in this review, the molecular characterization of lymphatic vascular development and our understanding of this vasculature's role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions. We propose that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body's response to a wide range of human diseases.


Assuntos
Vasos Linfáticos/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , História do Século XXI , Humanos , Linfonodos/imunologia , Linfonodos/metabolismo , Linfangiogênese , Doenças Linfáticas/genética , Doenças Linfáticas/história , Doenças Linfáticas/patologia , Metástase Linfática , Vasos Linfáticos/anatomia & histologia , Vasos Linfáticos/citologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
20.
Nat Commun ; 11(1): 2552, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439942

RESUMO

Whereas microglia are recognized as fundamental players in central nervous system (CNS) development and function, much less is known about macrophages of the peripheral nervous system (PNS). Here, by comparing gene expression across neural and conventional tissue-resident macrophages, we identified transcripts that were shared among neural resident macrophages as well as selectively enriched in PNS macrophages. Remarkably, PNS macrophages constitutively expressed genes previously identified to be upregulated by activated microglia during aging, neurodegeneration, or loss of Sall1. Several microglial activation-associated and PNS macrophage-enriched genes were also expressed in spinal cord microglia at steady state. We further show that PNS macrophages rely on IL-34 for maintenance and arise from both embryonic and hematopoietic precursors, while their expression of activation-associated genes did not differ by ontogeny. Collectively, these data uncover shared and unique features between neural resident macrophages and emphasize the role of nerve environment for shaping PNS macrophage identity.


Assuntos
Macrófagos/metabolismo , Microglia/metabolismo , Sistema Nervoso Periférico/imunologia , Animais , Linhagem da Célula , Sistema Nervoso Central/citologia , Sistema Nervoso Central/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ativação de Macrófagos/genética , Macrófagos/citologia , Camundongos , Especificidade de Órgãos , Sistema Nervoso Periférico/citologia
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