Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 60
Filtrar
1.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34479991

RESUMO

COVID-19 induces a robust, extended inflammatory "cytokine storm" that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNß directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNß reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNß/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.


Assuntos
Coronavirus/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/virologia , Macrófagos/metabolismo , Animais , COVID-19/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/genética , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais
2.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33779682

RESUMO

Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-ß regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB-mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II-induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Histona Desmetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Macrófagos/metabolismo , Angiotensina II/farmacologia , Animais , Modelos Animais de Doenças , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
3.
Pediatr Diabetes ; 22(2): 345-353, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33034097

RESUMO

BACKGROUND: Emerging adulthood presents unique challenges for type 1 diabetes (T1D) management. Barriers to achieving optimal diabetes outcomes have been studied but less is known about how emerging adults overcome these challenges. Characterizing emerging adults' protective factors may help guide T1D care during this developmental period. We anticipated identifying social, cognitive, and behavioral protective factors and were open to additional themes. METHODS: We analyzed transcripts from semi-structured qualitative interviews with 62 emerging adults (age 18-24 years) with T1D using hybrid thematic analysis. Interviews queried about participants' perspectives on diabetes management challenges, how they overcome challenges, and diabetes resilience. RESULTS: We categorized responses into three types of protective factors: (a) Social: Interpersonal strategies such as obtaining tangible support (especially from parents) and emotional support from friends, medical professionals, and community leaders. (b) Cognitive: Believing one can live a "normal" life with T1D, benefit-finding, and viewing diabetes management as an important part of life. (c) Behavioral: Proactively planning for diabetes challenges, maintaining a consistent routine while allowing for flexibility, balancing diabetes and non-diabetes activities, and using diabetes-specific and general technologies to support self-management. CONCLUSIONS: The adaptive approaches emerging adults with T1D use to handle the challenges of diabetes include seeking interpersonal support, managing their thoughts about T1D, and taking specific actions to prevent or resolve challenges. Helping emerging adults identify and strengthen their protective factors has potential to affect clinical outcomes. Strengths-based assessment and clinical attention to protective factors may prepare adolescents to successfully manage the challenges of transition to adult care.

4.
JCI Insight ; 5(17)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32879137

RESUMO

Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB-mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-ß-induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b-mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus/fisiopatologia , Dinoprostona/farmacologia , Epigênese Genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/prevenção & controle , Macrófagos/efeitos dos fármacos , Cicatrização , Idoso , Animais , Ciclo-Oxigenase 2/metabolismo , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Ocitócicos/farmacologia , Fenótipo , Pseudomonas aeruginosa/efeitos dos fármacos , Transdução de Sinais
5.
Eur J Immunol ; 50(12): 1929-1940, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32662520

RESUMO

Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4-/- ) or MyD88 (MyD88-/- ) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.


Assuntos
Histona Desmetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Macrófagos/metabolismo , Palmitatos/metabolismo , Receptor 4 Toll-Like/metabolismo , Cicatrização/fisiologia , Animais , Diabetes Mellitus Tipo 2 , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia
6.
J Vasc Surg ; 72(6): 1996-2005.e4, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32278573

RESUMO

OBJECTIVE: Widespread adoption of direct oral anticoagulants (DOACs) for atrial fibrillation and venous thromboembolism treatment has resulted in peripheral bypass patients receiving therapeutic anticoagulation with DOACs postoperatively. This study was undertaken to evaluate patient outcomes after open peripheral bypass based on anticoagulation treatment. METHODS: Postoperative treatment and outcomes of patients undergoing peripheral bypass operations between January 2012 and December 2017 from a statewide multicenter quality improvement registry were examined. Surgeons participating in the registry were surveyed on practice patterns regarding DOACs in bypass patients. Multivariate logistic regression was performed for 30-day transfusion outcomes, and multiple linear regression was performed for length of stay. RESULTS: Among 9682 patients, 7685 patients received no anticoagulation, whereas 1379 received a vitamin K antagonist (VKA) and 618 received a DOAC postoperatively. Patients receiving anticoagulation compared with no anticoagulation had a higher body mass index and were more likely to have preoperative anemia, congestive heart failure, and atrial fibrillation (all P < .001). Compared with patients receiving VKAs, patients receiving DOACs were less likely to have chronic kidney disease (P = .002) and more likely to have atrial fibrillation (P < .001). The shortest length of stay was among patients receiving no anticoagulation (median, 5 days; interquartile range, 3-9 days; P < .001), followed by DOACs (median, 6 days; interquartile range 3-11 days; P < .001) and VKAs (median, 8 days; interquartile range, 5-13 days; P < .001). Compared with patients receiving VKAs postoperatively, there was no difference in readmission for anticoagulation complications, bypass thrombectomy or thrombolysis, major amputation, or graft patency at 1 year among patients receiving DOACs. On multivariate logistic regression, patients receiving a DOAC (odds ratio, 0.743; confidence interval, 0.59-0.94; P = .011) or no anticoagulation (odds ratio, 0.792; confidence interval, 0.69-0.91; P = .001) were less likely to require transfusion within 30 days than patients taking VKAs. Approximately 70% of the surveyed surgeons reported that they "sometimes" or "always" use DOACs instead of VKAs for protection of a high-risk bypass. CONCLUSIONS: Among patients undergoing lower extremity surgical bypass, those receiving a DOAC postoperatively had a shorter length of stay and were less likely to receive a transfusion in 30 days without compromising graft patency and readmission for anticoagulation complications, thrombectomy, or thrombolysis or affecting amputation rate compared with those receiving a VKA. A majority of surgeons within the quality collaborative have adopted the use of DOACs after peripheral bypass, suggesting the need for a prospective trial evaluating DOAC safety and efficacy in patients requiring anticoagulation for high-risk bypass grafts.


Assuntos
Implante de Prótese Vascular , Inibidores do Fator Xa/uso terapêutico , Doença Arterial Periférica/cirurgia , Cuidados Pós-Operatórios , Trombose/prevenção & controle , Idoso , Implante de Prótese Vascular/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Tempo de Internação , Masculino , Michigan , Pessoa de Meia-Idade , Readmissão do Paciente , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Trombose/etiologia , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular
7.
J Immunol ; 204(9): 2503-2513, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32205424

RESUMO

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout (Mll1f/fLyz2Cre+ ), we determined that MLL1 drives Tlr4 expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the Tlr4 promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either Tlr4 (Tlr4-/- ) or myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Epigênese Genética/genética , Macrófagos/fisiologia , Receptor 4 Toll-Like/genética , Cicatrização/genética , Idoso , Animais , Epigênese Genética/imunologia , Feminino , Histonas/genética , Histonas/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/imunologia , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/imunologia , Receptor 4 Toll-Like/imunologia , Cicatrização/imunologia
8.
JCI Insight ; 5(5)2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32069267

RESUMO

A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines, such as TNF-α. Previous studies have shown that an altered epigenetic program directs diabetic macrophages toward a proinflammatory phenotype, contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyltransferase (HAT) that has been shown be a coactivator of TNF-α signaling and promote NF-κB-mediated gene transcription in prostate cancer cell lines. Based on MOF's role in TNF-α/NF-κB-mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used myeloid-specific Mof-knockout (Lyz2Cre Moffl/fl) and diet-induced obese (DIO) mice to determine the function of MOF in diabetic wound healing. MOF-deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOF's primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could be stimulated by TNF-α and that treatment with etanercept, an FDA-approved TNF-α inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to our knowledge to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNF-α inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.


Assuntos
Diabetes Mellitus Experimental/imunologia , Histona Acetiltransferases/metabolismo , Macrófagos/imunologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Diabetes Mellitus Experimental/fisiopatologia , Etanercepte/farmacologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Cicatrização/fisiologia
9.
J Am Acad Child Adolesc Psychiatry ; 59(1): 186-194, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30953734

RESUMO

OBJECTIVE: To describe the test construction procedure and evaluate the internal consistency, criterion-referenced validity, and diagnostic accuracy of the Child/Adolescent Self-Report Version of the UCLA PTSD Reaction Index for DSM-5 (RI-5) across 2 independent samples. METHOD: Study 1 examined the clarity, developmental appropriateness, acceptability of individual RI-5 items, and internal consistency and criterion-referenced validity of the full test. The study 1 sample included 486 youth recruited from 2 major US cities who completed the RI-5 and a measure of depression. Study 2 evaluated the reliability and diagnostic accuracy of the RI-5 in 41 treatment-seeking youth who completed the RI-5 and a "gold standard" structured diagnostic interview, the Clinician-Administered PTSD Scale for DSM-5-Child/Adolescent Version. RESULTS: RI-5 total scale scores showed excellent internal consistency in the 2 samples. Study 1 provided evidence of criterion-referenced validity, in that total scale scores correlated positively with depressive symptoms. Study 2 provided evidence of diagnostic accuracy (including discriminant-groups validity). RI-5 total scores discriminated youth with from youth without PTSD as benchmarked against the structured diagnostic interview. Further, receiver operating characteristic analyses using a total score of 35 provided excellent diagnostic classification accuracy (area under the curve 0.94). CONCLUSION: The developmental appropriateness and diagnostic accuracy of the RI-5 support its utility for clinical assessment, case conceptualization, and treatment planning in different child-serving systems, including schools, juvenile justice, child welfare, and mental health.


Assuntos
Manual Diagnóstico e Estatístico de Transtornos Mentais , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/psicologia , Adolescente , Criança , Depressão/diagnóstico , Depressão/psicologia , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes , Estados Unidos
10.
J Vasc Surg ; 71(5): 1741-1748.e2, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31831311

RESUMO

OBJECTIVE: A diverse array of measures are used to evaluate academic physicians. One critical factor is the scholarly influence an author has on the research discourse within a field. The National Institutes of Health recently developed the Relative Citation Ratio (RCR) as a method to quantify the influence of published research. The aim of this study was to examine the academic influence of vascular surgeons using RCR within common vascular disease research fields. METHODS: Using the PubMed and National Institutes of Health iCite databases, scientific fields of abdominal and thoracic aortic aneurysm, peripheral artery disease (PAD), cerebral vascular occlusive disease, deep venous thrombosis (DVT), and venous insufficiency were queried for the highest rated RCR articles in each category (2007-2012). To calculate the RCR, article citation rates are divided by an expected citation rate derived from performance of articles in the same field, with the resulting RCR being level and field independent. Article categories were divided into basic science, health services, and clinical research on the basis of two independent reviews. For articles, academic backgrounds of the first, second, and last authors ("influential authors") were collected analyzing procedural specialty: surgery, medicine subspecialty (cardiology, neurology, nephrology), radiology/engineering, and other (anesthesia and pediatrics). Statistical significance between scientific fields and academic background was determined using Student t-test or analysis of variance followed by Newman-Keuls post hoc test. RESULTS: The academic influence of vascular surgeons varied substantially by the scientific field. Vascular surgeons compared with medical specialists were found to have the highest academic influence in abdominal aortic aneurysm research, composing 51% of the influential authors on the highest rated RCR studies (5.9 ± 0.8 vs 5.6 ± 0.8; P = .6). In contrast, vascular surgeons composed only 13% of influential authors compared with medical specialists in DVT (RCR, 2.6 ± 0.3 vs 15.7 ± 1.7; P < .003) and 18% in PAD (RCR, 1.9 ± 0.5 vs 2.1 ± 0.2; P = .78) research fields. Grouping all vascular fields of study together, no difference in RCR was found between vascular surgery and radiology/engineering. However, the mean RCR was significantly lower for vascular surgeons compared with medical subspecialties (4.5 ± 0.4 vs 6.8 ± 0.5; P < .05). CONCLUSIONS: Vascular surgeons exhibit a moderate academic influence in the field of aneurysmal disease but lag behind medical subspecialists in high-impact scientific contributions to the fields of PAD and DVT. Innovative strategies and collaborations are likely needed to increase the influence of vascular surgeons on the academic discourse of several vascular disease research fields.


Assuntos
Pesquisa Biomédica , Bases de Dados Factuais , National Institutes of Health (U.S.) , Doenças Vasculares/cirurgia , Procedimentos Cirúrgicos Vasculares , Bibliometria , Humanos , Estados Unidos
11.
Thromb Haemost ; 120(2): 289-299, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31887775

RESUMO

Venous thrombosis (VT) resolution is a complex process, resembling sterile wound healing. Infiltrating blood-derived monocyte/macrophages (Mo/MΦs) are essential for the regulation of inflammation in tissue repair. These cells differentiate into inflammatory (CD11b+Ly6CHi) or proreparative (CD11b+Ly6CLo) subtypes. Previous studies have shown that infiltrating Mo/MΦs are important for VT resolution, but the precise roles of different Mo/MΦs subsets are not well understood. Utilizing murine models of stasis and stenosis inferior vena cava thrombosis in concert with a Mo/MΦ depletion model (CD11b-diphtheria toxin receptor [DTR]-expressing mice), we examined the effect of Mo/MΦ depletion on thrombogenesis and VT resolution. In the setting of an 80 to 90% reduction in circulating CD11b+Mo/MΦs, we demonstrated that Mo/MΦs are not essential for thrombogenesis, with no difference in thrombus size, neutrophil recruitment, or neutrophil extracellular traps found. Conversely, CD11b+Mo/MΦ are essential for VT resolution. Diphtheria toxoid (DTx)-mediated depletion after thrombus creation depleted primarily CD11b+Ly6CLo Mo/MΦs and resulted in larger thrombi. DTx-mediated depletion did not alter CD11b+Ly6CHi Mo/MΦ recruitment, suggesting a protective effect of CD11b+Ly6CLo Mo/MΦs in VT resolution. Confirmatory Mo/MΦ depletion with clodronate lysosomes showed a similar phenotype, with failure to resolve VT. Adoptive transfer of CD11b+Ly6CLo Mo/MΦs into Mo/MΦ-depleted mice reversed the phenotype, restoring normal thrombus resolution. These findings suggest that CD11b+Ly6CLo Mo/MΦs are essential for normal VT resolution, consistent with the known proreparative function of this subset, and that further study of Mo/MΦ subsets may identify targets for immunomodulation to accelerate and improve thrombosis resolution.


Assuntos
Lisossomos/metabolismo , Macrófagos/citologia , Monócitos/citologia , Trombose/sangue , Trombose Venosa/sangue , Transferência Adotiva , Animais , Antígenos Ly/metabolismo , Antígenos CD11/metabolismo , Separação Celular , Toxina Diftérica/farmacologia , Ensaio de Imunoadsorção Enzimática , Inflamação , Leucócitos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Fenótipo
12.
Arterioscler Thromb Vasc Biol ; 39(11): 2353-2366, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31644352

RESUMO

OBJECTIVE: Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined. Approach and Results: Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3-, CD19-, Ly6G-) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow-derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL [interleukin]-1ß, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow-derived macrophages and wound macrophages. This demonstrated decreased expression of Mll1, an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow-derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in MLL1 compared with nonseptic controls. CONCLUSIONS: These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1-mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.


Assuntos
Epigênese Genética , Inflamação/fisiopatologia , Macrófagos/fisiologia , Sepse/genética , Sepse/fisiopatologia , Cicatrização/fisiologia , Animais , Células da Medula Óssea/fisiologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Humanos , Tolerância Imunológica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Proteína de Leucina Linfoide-Mieloide/genética , NF-kappa B/genética , Regiões Promotoras Genéticas , Sepse/metabolismo
13.
Immunity ; 51(2): 258-271.e5, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31350176

RESUMO

Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) ß, and under diabetic conditions, this IFNß-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.


Assuntos
Proteínas de Transporte/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Macrófagos/fisiologia , Proteínas Nucleares/metabolismo , Idoso , Animais , Proteínas de Transporte/genética , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Fenótipo , Ácido Úrico/metabolismo , Cicatrização
15.
J Invest Dermatol ; 139(12): 2528-2537.e2, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31207226

RESUMO

Control of inflammation is critical for the treatment of nonhealing wounds, but a delicate balance exists between early inflammation that is essential for normal tissue repair and the pathologic inflammation that can occur later in the repair process. This necessitates the development of novel therapies that can target inflammation at the appropriate time during repair. Here, we found that SIRT3 is essential for normal healing and regulates inflammation in wound macrophages after injury. Under prediabetic conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation. In addition, we found that FABP4 regulates SIRT3 in human blood monocytes, and inhibition of FABP4 in wound macrophages decreases inflammatory cytokine expression, making FABP4 a viable target for the regulation of excess inflammation and wound repair in diabetes. Using a series of ex vivo and in vivo studies with genetically engineered mouse models and diabetic human monocytes, we showed that FABP4 expression is epigenetically upregulated in diabetic wound macrophages and, in turn, diminishes SIRT3 expression, thereby promoting inflammation. These findings have significant implications for controlling inflammation and promoting tissue repair in diabetic wounds.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Sirtuína 3/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL
16.
Curr Diab Rep ; 19(6): 27, 2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-31030356

RESUMO

PURPOSE OF REVIEW: Given the challenges achieving recommended glycemic targets in youth with type 1 diabetes (T1D), providers may consider recommending carbohydrate-restricted diets (CRDs) to optimize glycemic control. The goal of the present review is to describe relevant literature on the potential medical and psychosocial benefits and risks of CRDs in youth with T1D. RECENT FINDINGS: Limited data exist on the effects of CRDs in pediatric populations. Findings from studies with youth and adults are mixed; some indicate that CRDs may be associated with desirable medical outcomes, such as improved glycemic control and reduced HbA1c, which may contribute to positive psychological outcomes such as reduced diabetes distress and depressive symptoms. Others suggest that CRDs may also be associated with detrimental outcomes, including mineral deficiencies and suboptimal growth, and dietary restriction has been linked to greater diabetes distress, disordered eating, and diabetes management. More research is needed to evaluate benefits and risks of CRDs in youth. Providers should exercise caution when discussing CRDs with youth and families, particularly when considering CRDs for youth at elevated risk for eating disordered behavior.


Assuntos
Diabetes Mellitus Tipo 1 , Transtornos da Alimentação e da Ingestão de Alimentos , Adolescente , Glicemia , Criança , Depressão , Dieta com Restrição de Carboidratos , Humanos
17.
J Immunol ; 202(6): 1777-1785, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30710046

RESUMO

Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+ ) to determine MLL1 drives Tlr4 expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in Tlr4 (Tlr4-/- ), Myd88 (Myd88 -/-), and myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from Tlr4-/- and Myd88 -/- wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wild-type mice trafficked to wounds with restoration of normal healing and myeloid cell function in Tlr4-deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Pele/metabolismo , Receptor 4 Toll-Like/biossíntese , Cicatrização/fisiologia , Animais , Metilação de DNA/fisiologia , Feminino , Regulação da Expressão Gênica/fisiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/fisiologia , Pele/lesões
18.
Arterioscler Thromb Vasc Biol ; 39(4): 623-634, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760015

RESUMO

Cardiometabolic and vascular disease, with their associated secondary complications, are the leading cause of morbidity and mortality in Western society. Chronic inflammation is a common theme that underlies initiation and progression of cardiovascular disease. In this regard, monocytes/macrophages are key players in the development of a chronic inflammatory state. Over the past decade, epigenetic modifications, such as DNA methylation and posttranslational histone processing, have emerged as important regulators of immune cell phenotypes. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter monocyte/macrophage phenotypes in response to environmental stimuli. In this review, we highlight the current paradigms of monocyte/macrophage polarization and the emerging role of epigenetic modification in the regulation of monocyte/macrophage phenotype in obesity, diabetes mellitus, atherosclerosis, and abdominal aortic aneurysms.


Assuntos
Doenças Cardiovasculares/genética , Epigênese Genética , Inflamação/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Tecido Adiposo/patologia , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aterosclerose/metabolismo , Doenças Cardiovasculares/metabolismo , Citocinas/metabolismo , Metilação de DNA , Diabetes Mellitus/metabolismo , Código das Histonas , Humanos , Ativação de Macrófagos , Obesidade/metabolismo , Obesidade/patologia , Fenótipo , RNA não Traduzido/genética , Cicatrização
19.
Ann Vasc Surg ; 54: 72-83, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30267915

RESUMO

BACKGROUND: Safe resection of intraabdominal and retroperitoneal malignancies with a goal of negative margins may require vascular surgical assistance with grafting of the aorta and/or vena cava. The current report reviews malignancies associated with major vascular reconstructions at a single tertiary referral center. METHODS: Adults with abdominal or retroperitoneal tumors involving the aorta, vena cava, or iliac arteries that underwent reconstruction with vascular grafts at the University of Michigan from 2010 to 2016 were reviewed retrospectively. The initial presentation, surgical management, and outcomes were analyzed. RESULTS: Twelve patients with tumors involving the abdominal aorta, vena cava, or iliac arteries underwent major vascular reconstruction in this seven-year study period. Tumor pathology included solid tumors (leiomyosarcoma [n = 7], germ cell tumor [n = 3], and intravascular lymphoma [n = 2]). Surgical treatment included grafting of the vena cava (n = 6), aorta (n = 3), iliac artery (n = 4), or both the aorta and vena cava (n = 1). Patients with intravascular lymphoma were identified incidentally during treatment of abdominal aortic aneurysm or on pathological analysis of thromboembolism from an aortic source. Other patients had planned resection. Follow-up ranged from 9 to 86 months (median: 28.9). There were no graft occlusions. Tumor metastasized or recurred in patients with sarcoma (n = 2; 28.6%), germ cell tumor (n = 1; 33.3%), and intravascular lymphoma (n = 2; 100%). Both patients with lymphoma had multiple anastomotic or tumor-embolic pseudoaneurysms for <14 months after vascular reconstruction. Both lymphoma patients died during follow-up. CONCLUSIONS: This single-center review suggests that sarcoma and germ cell tumors may be safely resected in conjunction with major vascular reconstruction in carefully selected patients. In comparison, intravascular lymphoma identified incidentally at the time of aortic reconstruction resulted in a more malignant course with pseudoaneurysm formation of anastomoses or native vessels, cancer recurrence, and 100% mortality. Aneurysm contents and emboli should be carefully reviewed perioperatively by pathologists.


Assuntos
Neoplasias Abdominais/cirurgia , Aorta Abdominal/cirurgia , Implante de Prótese Vascular , Procedimentos Endovasculares , Artéria Ilíaca/cirurgia , Leiomiossarcoma/cirurgia , Linfoma/cirurgia , Neoplasias Embrionárias de Células Germinativas/cirurgia , Procedimentos Cirúrgicos Reconstrutivos , Neoplasias Retroperitoneais/cirurgia , Veia Cava Inferior/cirurgia , Neoplasias Abdominais/diagnóstico por imagem , Neoplasias Abdominais/mortalidade , Neoplasias Abdominais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Artéria Ilíaca/diagnóstico por imagem , Artéria Ilíaca/patologia , Achados Incidentais , Leiomiossarcoma/diagnóstico por imagem , Leiomiossarcoma/mortalidade , Leiomiossarcoma/patologia , Linfoma/diagnóstico por imagem , Linfoma/mortalidade , Linfoma/patologia , Masculino , Michigan , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/patologia , Fenótipo , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Procedimentos Cirúrgicos Reconstrutivos/mortalidade , Neoplasias Retroperitoneais/diagnóstico por imagem , Neoplasias Retroperitoneais/mortalidade , Neoplasias Retroperitoneais/patologia , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia de Intervenção , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/patologia
20.
Transl Res ; 204: 39-50, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30392877

RESUMO

Impaired wound healing is a major secondary complication of type 2 diabetes that often results in limb loss and disability. Normal tissue repair progresses through discrete phases including hemostasis, inflammation, proliferation, and remodeling. In diabetes, normal progression through these phases is impaired resulting in a sustained inflammatory state and dysfunctional epithelialization in the wound. Due to their plasticity, macrophages play a critical role in the transition from the inflammation phase to the proliferation phase. Diabetes disrupts macrophage function by impairing monocyte recruitment to the wound, reducing phagocytosis, and prohibiting the transition of inflammatory macrophages to an anti-inflammatory state. Diabetes also impedes keratinocyte and fibroblast function during the later phases resulting in impaired epithelialization of the wound. Several recent studies suggest that altered epigenetic regulation of both immune and structural cells in wounds may influence cell phenotypes and healing, particularly in pathologic states, such as diabetes. Specifically, it has been shown that macrophage plasticity during wound repair is partly regulated epigenetically and that diabetes alters this epigenetic regulation and contributes to a sustained inflammatory state. Epigenetic regulation is also known to regulate keratinocyte and fibroblast function during wound repair. In this review, we provide an introduction to the epigenetic mechanisms that regulate tissue repair and highlight recent findings that demonstrate, how epigenetic events are altered during the course of diabetic wound healing.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Pé Diabético/fisiopatologia , Epigênese Genética , Cicatrização/fisiologia , Animais , Plasticidade Celular , Montagem e Desmontagem da Cromatina , Metilação de DNA , Fibroblastos/fisiologia , Histonas/metabolismo , Humanos , Macrófagos/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...