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1.
Int J Mol Sci ; 24(10)2023 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-37239997

RESUMO

Alcohol misuse, directly or indirectly as a result of its metabolism, negatively impacts most tissues, including four with critical roles in energy metabolism regulation: the liver, pancreas, adipose, and skeletal muscle. Mitochondria have long been studied for their biosynthetic roles, such as ATP synthesis and initiation of apoptosis. However, current research has provided evidence that mitochondria participate in myriad cellular processes, including immune activation, nutrient sensing in pancreatic ß-cells, and skeletal muscle stem and progenitor cell differentiation. The literature indicates that alcohol impairs mitochondrial respiratory capacity, promoting reactive oxygen species (ROS) generation and disrupting mitochondrial dynamics, leading to dysfunctional mitochondria accumulation. As discussed in this review, mitochondrial dyshomeostasis emerges at a nexus between alcohol-disrupted cellular energy metabolism and tissue injury. Here, we highlight this link and focus on alcohol-mediated disruption of immunometabolism, which refers to two distinct, yet interrelated processes. Extrinsic immunometabolism involves processes whereby immune cells and their products influence cellular and/or tissue metabolism. Intrinsic immunometabolism describes immune cell fuel utilization and bioenergetics that affect intracellular processes. Alcohol-induced mitochondrial dysregulation negatively impacts immunometabolism in immune cells, contributing to tissue injury. This review will present the current state of literature, describing alcohol-mediated metabolic and immunometabolic dysregulation from a mitochondrial perspective.


Assuntos
Etanol , Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Etanol/efeitos adversos , Etanol/metabolismo , Metabolismo Energético , Obesidade/metabolismo
2.
Alcohol Clin Exp Res ; 46(11): 2041-2053, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36124866

RESUMO

BACKGROUND: Antiretroviral therapy has improved life expectancy among people living with HIV (PLWH). Despite increased longevity, PLWH are at increased risk of age-related comorbidities, including frailty. We examined the relationship between body composition and frailty among PLWH, and moderation of this relationship by substance use, physical activity (PA), and physical function. METHODS: Participants (n = 341; 71% male, 48 ± 10 years, body mass index (BMI) = 27.3 ± 7.0 kg/m2 ) enrolled in the New Orleans Alcohol Use in HIV (NOAH) study underwent measures of body composition, muscle strength, and gait speed. Whole blood phosphatidylethanol (PEth) was measured, and substance use and PA were self-reported. Frailty risk measures included the 58-Item Deficit Index (DI58) and the Veterans Aging Cohort Study (VACS) Index 1.0, where higher scores indicate greater frailty risk. RESULTS: Multivariable linear regression adjusted for age, sex, and race showed that higher fat-free mass index (FFMI), body fat (%), waist-to-hip ratio, and body mass index (BMI) ≥ 25.0 kg/m2 vs. < 25.0 kg/m2 were significantly (p < 0.05) associated with decreased frailty risk measured by the VACS Index, whereas adjusted analyses showed no association between body composition variables and the DI58 score. Recent alcohol use, muscle strength, and PA, but not lifetime alcohol use or gait speed, significantly moderated associations between body composition variables and frailty risk with medium-to-large effect sizes. Subgroup analyses revealed a negative relationship between DI58 and FFMI among people with PEth > 8 ng/ml and negative relationships of VACS Index with FFMI and WHR in people with lower muscle strength. Overweight or obese BMI categories were positively associated with DI58 in people with lower muscle strength or higher PA level but negatively associated in those with higher muscle strength. CONCLUSIONS: Our findings indicate that body composition has significant modulatory effects on frailty risk in PLWH, where obesity increases the risk of frailty and greater muscle mass may be protective, even in individuals who use alcohol. These results highlight the importance of considering body composition, physical activity, and physical function in assessing frailty risk in PLWH, particularly among individuals who use alcohol. Moreover, they support the implementation of physical activity interventions to ameliorate the risk of frailty in aging PLWH.


Assuntos
Fragilidade , Infecções por HIV , Humanos , Masculino , Feminino , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Estudos de Coortes , Estudos Transversais , Composição Corporal/fisiologia , Força Muscular/fisiologia , Exercício Físico , Obesidade , Infecções por HIV/epidemiologia
3.
Microbiol Immunol ; 66(6): 330-341, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35067963

RESUMO

The gut microbiota has a fundamental role in the development and the maturation of the host immune system. Both innate and adaptive immune cells have critical functions in microbial pathogen containment and clearance, but the regulation of the commensal microbiome ecosystem in the gastrointestinal tract by these major immune cell populations is incompletely defined. The role of specific innate and adaptive immune cell in the regulation of the microbiota in the intestinal tract biogeographically was investigated. Dendritic cells, macrophages, CD4+ T-cells, CD8+ T-cells, and B-cells were depleted using monoclonal antibodies and clodronate liposomes, and the microbial communities were determined by 16S rRNA gene sequencing. With specific immune cell depletion, distinct microbiota changes were observed. In general, immune cell depleted mice had higher microbiota richness and evenness at all gut anatomical sites. At each gut segment, samples from immune cell-depleted animals clustered away from the isotype/liposome control mice. This was especially dramatic for the small intestinal microbiota. Specifically, Enterobacteriaceae, Bacteroides acidifaciens, and Mucispirillum schaedleri were highly enriched in the mucosa and lumen of the small intestine in immune cell-deficient animals. Further, the mucosal microbiota had higher microbiota evenness compared with luminal microbiota at all gut segments, and the UniFrac distance between B cell depleted and isotype control mice was the largest in the duodenum followed by the ileum and colon. Taken together, the data suggest that innate and adaptive immune cells specifically contribute to the regulation of the gut microbiota's biogeographical distribution along the gastrointestinal tract, and microbiota in the duodenum mucosa are more responsive to host immune changes compared with other anatomical sites.


Assuntos
Microbioma Gastrointestinal , Microbiota , Imunidade Adaptativa , Animais , Linfócitos T CD4-Positivos , Imunidade Inata , Camundongos , RNA Ribossômico 16S/genética
4.
J Infect Dis ; 223(6): 1029-1039, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-32725203

RESUMO

BACKGROUND: Inflammation persists among persons with human immunodeficiency virus (PWH) despite effective antiretroviral therapy and may contribute to T-cell dysfunction. Alcohol use is prevalent among PWH and promotes intestinal leak, dysbiosis, and a proinflammatory milieu. Whether alcohol use is associated with T-cell late differentiation remains to be investigated. METHODS: Data and samples from PWH (N = 359 of 365) enrolled in the New Orleans Alcohol Use in HIV Study were used. Alcohol use was assessed by self-report (Alcohol Use Disorders Identification Test; lifetime alcohol exposure; 30-day Alcohol Timeline Followback) and phosphatidylethanol (PEth) quantitation. In a subset of participants, fecal bacterial content was assessed by ribosomal 16S marker gene deep sequencing and quantitative polymerase chain reaction. Intestinal leak was assessed by fecal-to-plasma α-1-antitrypsin (A1AT) enzyme-linked immunosorbent assay ratio. Peripheral T-cell populations were quantified by flow cytometry. RESULTS: Alcohol Use Disorder Identification Test scores were positively associated with activated-senescent, exhausted, and terminal effector memory CD45RA+CD8+ but not CD4+ T cells (cells/µL) after confounder adjustment (P < .050). Phosphatidylethanol was positively associated with A1AT (P < .050). The PEth and activated-senescent CD8+ were associated with bacterial ß-diversity (P < .050) and positively associated with the relative abundance of coabundant Prevotellaceae members (q < .100). CONCLUSIONS: Alcohol use among PWH is associated with CD8+ T-cell late differentiation, intestinal leak, and dysbiosis. Alcohol-associated dysbiosis is implicated in CD8+ T-cell senescence.


Assuntos
Alcoolismo , Linfócitos T CD8-Positivos/classificação , Disbiose , Infecções por HIV , Alcoolismo/complicações , Disbiose/complicações , Infecções por HIV/complicações , Humanos , Fenótipo
5.
Alcohol Clin Exp Res ; 45(5): 934-947, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33704802

RESUMO

BACKGROUND: Chronic alcohol consumption is associated with a compromised innate and adaptive immune responses to infectious disease. Mucosa-associated invariant T (MAIT) cells play a critical role in antibacterial host defense. However, whether alcohol-associated deficits in innate and adaptive immune responses are mediated by alterations in MAIT cells remains unclear. METHODS: To investigate the impact of alcohol on MAIT cells, mice were treated with binge-on-chronic alcohol for 10 days and sacrificed at day 11. MAIT cells in the barrier organs (lung, liver, and intestine) were characterized by flow cytometry. Two additional sets of animals were used to examine the involvement of gut microbiota on alcohol-induced MAIT cell changes: (1) Cecal microbiota from alcohol-fed (AF) mice were adoptive transferred into antibiotic-pretreated mice and (2) AF mice were treated with antibiotics during the experiment. MAIT cells in the barrier organs were measured via flow cytometry. RESULTS: Binge-on-chronic alcohol feeding led to a significant reduction in the abundance of MAIT cells in the barrier tissues. However, CD69 expression on tissue-associated MAIT cells was increased in AF mice compared with pair-fed (PF) mice. The expression of Th1 cytokines and the corresponding transcriptional factor was tissue specific, showing downregulation in the intestine and increases in the lung and liver in AF animals. Transplantation of fecal microbiota from AF mice resulted in a MAIT cell profile aligned to that of AF mouse donor. Antibiotic treatment abolished the MAIT cell differences between AF and PF animals. CONCLUSION: MAIT cells in the intestine, liver, and lung are perturbed by alcohol use and these changes are partially attributable to alcohol-associated dysbiosis. MAIT cell dysfunction may contribute to alcohol-induced innate and adaptive immunity and consequently end-organ pathophysiology.


Assuntos
Alcoolismo/imunologia , Consumo Excessivo de Bebidas Alcoólicas/imunologia , Depressores do Sistema Nervoso Central/farmacologia , Disbiose/imunologia , Etanol/farmacologia , Microbioma Gastrointestinal , Células T Invariantes Associadas à Mucosa/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Antígenos CD/efeitos dos fármacos , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/efeitos dos fármacos , Antígenos de Diferenciação de Linfócitos T/metabolismo , Transplante de Microbiota Fecal , Citometria de Fluxo , Mucosa Intestinal/citologia , Lectinas Tipo C/efeitos dos fármacos , Lectinas Tipo C/metabolismo , Fígado/citologia , Fígado/imunologia , Pulmão/citologia , Pulmão/imunologia , Camundongos , Células T Invariantes Associadas à Mucosa/imunologia
6.
Alcohol Clin Exp Res ; 44(6): 1261-1272, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32441814

RESUMO

BACKGROUND: High frequency of alcohol use among people living with HIV (PLWH) warrants careful assessment and screening to better understand its impact on HIV disease progression and development of comorbidities. Due to the limitations of the tools used to measure alcohol use, the links to health consequences are not fully understood. METHODS: We completed a cross-sectional analysis to examine the prevalence of alcohol consumption using multiple alcohol assessment tools and their correlation and consistency in a cohort of PLWH (N = 365) enrolled in the New Orleans Alcohol Use in HIV (NOAH) Study. Alcohol use was assessed with the Alcohol Use Disorders Identification Test (AUDIT), timeline followback (TLFB) Calendar, lifetime drinking history, Alcohol and Drug Addiction Severity Index, and blood levels of phosphatidylethanol (PEth). Spearman's correlations were estimated for continuous measures of alcohol consumption; Wilcoxon rank-sum tests were used to compare means; and logistic regression was used to estimate odds of alcohol use by demographic characteristics. RESULTS: Self-report of current alcohol use varied from 58.9 to 73.7% depending on the assessment. All the self-reported alcohol measures showed statistically significant correlations with the biological marker PEth. The highest correlation was with TLFB grams (r = 0.67, p < 0.001). Using TLFB, 73.7% of the cohort reported using alcohol in the last 30 days, and 61.6% had a positive PEth value. The prevalence of risky drinkers, meeting the TLFB > 3 (women) or >4 (men) drinks/day or>7 (women) or>14 (men) drinks/week, was 49.0%. Medium-risk drinking defined as an AUDIT score ≥ 8 was reported in 40.3%, and high-risk drinkers/probable AUD (AUDIT score ≥ 16) was met by 17.0% of the cohort. CONCLUSIONS: Our results demonstrate the importance of comprehensive assessments for alcohol use, including self-report via multiple assessment tools administered by trained staff, as well as the addition of biomarkers for improved classification of subjects into different drinking categories.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/epidemiologia , Infecções por HIV/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/sangue , Alcoolismo/sangue , Estudos Transversais , Feminino , Glicerofosfolipídeos/sangue , Ambiente Domiciliar , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Nova Orleans/epidemiologia , Autorrelato , Adulto Jovem
7.
Alcohol Clin Exp Res ; 43(4): 704-709, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30748025

RESUMO

BACKGROUND: Alcohol use disorders (AUDs) are highly prevalent in people living with HIV (PLWH) and are associated with increased HIV risk behaviors, suboptimal treatment adherence, potential interaction with medication pharmacodynamics, and greater risk for disease progression. Preclinical studies show that chronic binge alcohol administration accelerates disease progression and aggravates pathogenesis in the simian immunodeficiency virus (SIV)-infected rhesus macaque model despite viral suppression by antiretroviral therapy. METHODS: To translate preclinical findings in the rhesus macaque model of chronic binge alcohol administration and SIV infection and to address areas of uncertainty surrounding the biological mechanisms and socioenvironmental modifiers that contribute to the relationship between alcohol use and HIV-associated comorbidities, precocious aging, and disease progression, we designed a translational multiproject, longitudinal, cohort study, and the New Orleans Alcohol Use in HIV (NOAH) Study. The NOAH Study is led by a multidisciplinary team of scientists, with a research focus on the interaction of AUD and HIV. The overarching hypothesis is that alcohol use will lead to adverse health outcomes in PLWH. In this report, we describe the study design and baseline descriptive characteristics of our cohort. RESULTS: Three-hundred and sixty-five participants completed the baseline testing. The cohort is predominantly male (69%) and African American (83.5%). The majority of participants report incomes below 200% of the federal poverty level. CD4 counts <200 cells/µl were found in 12.8% and viral loads <50 copies/ml were found in 73.6%. These HIV status variables did not differ based upon alcohol use. CONCLUSIONS: The NOAH Study facilitates bidirectional translational investigation of alcohol's impact on PLWH. Translation of preclinical findings to PLWH permits confirmation of basic biological mechanisms in humans and also allows incorporation of sociobehavioral factors that may affect biology but are challenging to replicate in preclinical models.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Projetos de Pesquisa , Pesquisa Translacional Biomédica/métodos , Adulto , Idoso , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Multimorbidade , Nova Orleans/epidemiologia , Fatores de Risco , Adulto Jovem
8.
Alcohol Clin Exp Res ; 39(8): 1380-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26147204

RESUMO

BACKGROUND: The digestive tract lymphatics transport approximately two-thirds of all lymph produced in the body and have a key role in mucosal immunity through their contribution to antigen transport and immune cell trafficking. Mesenteric lymphatic pumping function integrity is critical for maintaining homeostasis and lipid transport. We previously demonstrated that acute alcohol intoxication (AAI) increases mesenteric lymphatic amplitude of contraction and ejection fraction, enhancing the ability of the lymphatic vessels to pump lymph. AAI has been shown to disrupt intestinal barrier integrity, which would be expected to increase the endotoxin content of mesenteric lymph. In this study, we tested the prediction that AAI increases lymphatic permeability directly affecting perilymphatic adipose tissue (PLAT) milieu. METHODS: Male Sprague Dawley rats received an intragastric infusion of 2.5 g/kg of alcohol. Isovolumic administration of water (vehicle) served as control. PLAT was isolated for the determination of Evans Blue extravasation (permeability), cytokine content, and immunohistochemistry for inflammatory cell infiltration at 30 minutes and 24 hours after alcohol administration. RESULTS: PLAT isolated from AAI animals had greater Evans Blue concentrations and cytokine expression (24 hours post-AAI) and mast cell and neutrophil density than that isolated from controls. AAI resulted in significantly higher plasma lipopolysaccharide (endotoxin) levels, lower plasma adiponectin levels (at 30 minutes), and unchanged plasma visfatin levels. CONCLUSIONS: The data indicate that AAI induces mesenteric lymphatic hyperpermeability, promotes PLAT inflammatory milieu and disrupts the systemic adipokine profile. These findings suggest an association between alcohol-induced lymphatic hyperpermeability and early manifestations of metabolic dysfunction as a result of alcohol abuse. We propose that crosstalk between lymph and PLAT results in adipose inflammation and adipokine dysregulation during AAI.


Assuntos
Tecido Adiposo/metabolismo , Intoxicação Alcoólica/metabolismo , Etanol/toxicidade , Vasos Linfáticos/metabolismo , Mesentério/metabolismo , Adipocinas/biossíntese , Tecido Adiposo/patologia , Intoxicação Alcoólica/patologia , Animais , Etanol/administração & dosagem , Vasos Linfáticos/patologia , Masculino , Mesentério/efeitos dos fármacos , Mesentério/patologia , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
9.
Alcohol Clin Exp Res ; 38(7): 1993-2000, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24942272

RESUMO

BACKGROUND: Chronic alcohol intoxication suppresses immune function and increases osteoporosis risk suggesting bone-tissue cytotoxicity. Human immunodeficiency virus infection leads to similar impairments. This study investigated the effects of chronic alcohol administration during the early stage of simian immunodeficiency virus (SIV) infection on hematopoietic stem and progenitor cells (HSPCs) and their differentiated progeny in the bone marrow and peripheral blood of rhesus macaques. METHODS: Rhesus macaques were administered alcohol or sucrose daily for a period of 3 months prior to intrarectal inoculation with 250 TCID50 of SIVmac251 . Bone marrow aspirates and blood samples were taken prior to and 2 weeks after SIV infection. Bone marrow cells (BMCs) were assessed using flow cytometric phenotyping for upstream HSPCs and for differentiated cells of the monocyte-granulocyte lineages. Likewise, cells were quantitated in peripheral blood. RESULTS: Of the bone marrow HSPCs, only the common lymphoid progenitor (CLP) was altered by alcohol administration pre-SIV (38 ± 9.4/10(6) BMCs vs. 226 ± 64.1/10(6) BMCs, sucrose vs. alcohol). Post-SIV, the frequency of CLPs in the bone marrow of alcohol-administered macaques decreased compared with the sucrose-administered macaques (107 ± 47.6/10(6) BMCs vs. 43 ± 16.3/10(6) BMCs). However, marrow mature cells of the monocyte lineage, specifically macrophages and osteoclast progenitors, were increased by both chronic alcohol administration and SIV infection (287% and 662%, respectively). As expected, mature cells such as granulocytes (polymorphonuclear cells), B cells, and CD4+ T cells in the peripheral blood were decreased by SIV infection (37 to 62% decline from preinfection), but not affected after 3 months of chronic alcohol administration. CONCLUSIONS: Chronic alcohol administration disrupts myelomonocytic development in the bone marrow during the early period of SIV infection promoting macrophage and osteoclast lineages. We predict this shift in CLP:macrophage/osteoclast balance creates an environment that favors bone resorption and immunosuppression.


Assuntos
Alcoolismo/patologia , Alcoolismo/fisiopatologia , Etanol/administração & dosagem , Etanol/efeitos adversos , Mielopoese/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Alcoolismo/sangue , Alcoolismo/complicações , Animais , Medula Óssea/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Macaca mulatta , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/sangue
10.
J Immunol ; 188(4): 1961-9, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22238460

RESUMO

Enhancement of stem cell Ag-1 (Sca-1) expression by myeloid precursors promotes the granulopoietic response to bacterial infection. However, the underlying mechanisms remain unclear. ERK pathway activation strongly enhances proliferation of hematopoietic progenitor cells. In this study, we investigated the role of Sca-1 in promoting ERK-dependent myeloid lineage proliferation and the effects of alcohol on this process. Thirty minutes after i.p. injection of alcohol, mice received i.v. challenge with 5 × 10(7) Escherichia coli for 8 or 24 h. A subset of mice received i.v. BrdU injection 20 h after challenge. Bacteremia increased Sca-1 expression, ERK activation, and proliferation of myeloid and granulopoietic precursors. Alcohol administration suppressed this response and impaired granulocyte production. Sca-1 expression positively correlated with ERK activation and cell cycling, but negatively correlated with myeloperoxidase content in granulopoietic precursors. Alcohol intoxication suppressed ERK activation in granulopoietic precursors and proliferation of these cells during bacteremia. Granulopoietic precursors in Sca-1(-/-) mice failed to activate ERK signaling and could not increase granulomacrophagic CFU activity following bacteremia. These data indicate that Sca-1 expression promotes ERK-dependent myeloid cell proliferation during bacteremia. Suppression of this response could represent an underlying mechanism for developing myelosuppression in alcohol-abusing hosts with severe bacterial infection.


Assuntos
Intoxicação Alcoólica/imunologia , Antígenos Ly/imunologia , Bacteriemia/imunologia , Etanol/farmacologia , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/imunologia , Células Mieloides/metabolismo , Animais , Antígenos Ly/biossíntese , Antígenos Ly/metabolismo , Proliferação de Células/efeitos dos fármacos , Escherichia coli/imunologia , Escherichia coli/patogenicidade , Infecções por Escherichia coli/imunologia , Granulócitos/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Células Mieloides/efeitos dos fármacos , Peroxidase/biossíntese , Transdução de Sinais
11.
Matrix Biol ; 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39368561

RESUMO

The heparan sulfate (HS) 6-O-endosulfatases or the Sulfs (Sulf1 and Sulf2) are the only known enzymes that can modify HS sulfation status extracellularly and have been shown to regulate diverse biological processes. The role of the Sulfs in bone marrow (BM) hematopoiesis is not known. In this study, we generated a novel mouse line with myeloid-specific deletion of the Sulfs by crossing Sulf1/2 double floxed mice with the LysM-cre line. The LysM-Sulf knockout (KO) male mice exhibited age-dependent expansion of hematopoietic stem cells and the granulocyte-monocyte lineages in the BM, whereas common lymphoid progenitors and B lymphocyte populations were significantly reduced. Although megakaryocytic and erythroid progenitors were not reduced in the BM, the LysM-Sulf KO males suffered age-dependent reduction of red blood cells (RBCs) and platelets in the peripheral blood, suggesting that the production of RBCs and platelets was arrested at later stages. In addition, LysM-Sulf KO males displayed progressive splenomegaly with extramedullary hematopoiesis. Compared to males, LysM-Sulf KO females exhibited a much-reduced phenotype, and ovariectomy had little effect. Mechanistically, reduced TGF-ß/Smad2 but enhanced p53/p21 signaling were observed in male but not female LysM-Sulf KO mice. Finally, HS disaccharide analysis via LC-MS/MS revealed increased HS 6-O-sulfation in the BM from both male and female LysM-Sulf KO mice, however, the distribution of 6-O-sulfated motifs were different between the sexes with compensatory increase in Sulf1 expression observed only in LysM-Sulf KO females. In conclusion, our study reveals that myeloid deficiency of the Sulfs leads to multilineage abnormalities in BM hematopoiesis in an age- and sex-dependent manner.

12.
Front Immunol ; 15: 1368099, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38665923

RESUMO

Early increase in the level of endothelial progenitor cells (EPCs) in the systemic circulation occurs in patients with septic infection/sepsis. The significance and underlying mechanisms of this response remain unclear. This study investigated the bone marrow EPC response in adult mice with septic infection induced by intravenous injection (i.v.) of Escherichia coli. For in vitro experiments, sorted marrow stem/progenitor cells (SPCs) including lineage(lin)-stem cell factor receptor (c-kit)+stem cell antigen-1 (Sca-1)-, lin-c-kit+, and lin- cells were cultured with or without lipopolysaccharides (LPSs) and recombinant murine vascular endothelial growth factor (VEGF) in the absence and presence of anti-Sca-1 crosslinking antibodies. In a separate set of experiments, marrow lin-c-kit+ cells from green fluorescence protein (GFP)+ mice, i.v. challenged with heat-inactivated E. coli or saline for 24 h, were subcutaneously implanted in Matrigel plugs for 5 weeks. Marrow lin-c-kit+ cells from Sca-1 knockout (KO) mice challenged with heat-inactivated E. coli for 24 h were cultured in the Matrigel medium for 8 weeks. The marrow pool of EPCs bearing the lin-c-kit+Sca-1+VEGF receptor 2 (VEGFR2)+ (LKS VEGFR2+) and LKS CD133+VEGFR2+ surface markers expanded rapidly following septic infection, which was supported by both proliferative activation and phenotypic conversion of marrow stem/progenitor cells. Increase in marrow EPCs and their reprogramming for enhancing angiogenic activity correlated with cell-marked upregulation of Sca-1 expression. Sca-1 was coupled with Ras-related C3 botulinum toxin substrate 2 (Rac2) in signaling the marrow EPC response. Septic infection caused a substantial increase in plasma levels of IFN-γ, VEGF, G-CSF, and SDF-1. The early increase in circulating EPCs was accompanied by their active homing and incorporation into pulmonary microvasculature. These results demonstrate that the marrow EPC response is a critical component of the host defense system. Sca-1 signaling plays a pivotal role in the regulation of EPC response in mice with septic infection.


Assuntos
Células Progenitoras Endoteliais , Proteínas de Membrana , Sepse , Animais , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/imunologia , Sepse/imunologia , Sepse/metabolismo , Camundongos , Camundongos Knockout , Escherichia coli/imunologia , Infecções por Escherichia coli/imunologia , Camundongos Endogâmicos C57BL , Fator A de Crescimento do Endotélio Vascular/metabolismo , Antígenos Ly/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/imunologia , Células Cultivadas , Masculino
13.
Infect Immun ; 81(6): 2197-205, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23545304

RESUMO

In response to severe bacterial infection, bone marrow hematopoietic activity shifts toward promoting granulopoiesis. The underlying cell signaling mechanisms remain obscure. To study the role of Toll-like receptor 4 (TLR4)/stem cell antigen-1 (Sca-1) signaling in this process, bacteremia was induced in mice by intravenous injection of Escherichia coli. A subgroup of animals also received intravenous 5-bromo-2-deoxyuridine (BrdU). In a separate set of experiments, bone marrow lineage-negative (lin(-)) stem cell growth factor receptor-positive (c-kit(+)) Sca-1(-) cells containing primarily common myeloid progenitors were cultured in vitro without or with E. coli lipopolysaccharide (LPS). In genotypic background control mice, bacteremia significantly upregulated Sca-1 expression by lin(-) c-kit(+) cells, as reflected by a marked increase in BrdU-negative lin(-) c-kit(+) Sca-1(+) cells in the bone marrow. In mice with the TLR4 gene deletion, this bacteremia-evoked Sca-1 response was blocked. In vitro, LPS induced a dose-dependent increase in Sca-1 expression by cultured marrow lin(-) c-kit(+) Sca-1(-) cells. LPS-induced upregulation of Sca-1 expression was regulated at the transcriptional level. Inhibition of c-Jun N-terminal kinase/stress-activated protein kinase (JNK) activity with the specific inhibitor SP600125 suppressed LPS-induced upregulation of Sca-1 expression by marrow lin(-) c-kit(+) Sca-1(-) cells. Engagement of Sca-1 with anti-Sca-1 antibodies enhanced the expression of Sfpi1 spleen focus-forming virus (SFFV) proviral integration 1 (PU.1) in marrow lin(-) c-kit(+) Sca-1(-) cells cultured with LPS. Sca-1 null mice failed to maintain the marrow pool of granulopoietic cells following bacteremia. These results demonstrate that TLR4/Sca-1 signaling plays an important role in the regulation of hematopoietic precursor cell programming and their enhancement of granulocyte lineage commitment in response to E. coli bacteremia.


Assuntos
Antígenos Ly/metabolismo , Bacteriemia/patologia , Infecções por Escherichia coli/patologia , Granulócitos/citologia , Células-Tronco Hematopoéticas/citologia , Proteínas de Membrana/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Antígenos Ly/genética , Escherichia coli , Regulação da Expressão Gênica , Granulócitos/fisiologia , Células-Tronco Hematopoéticas/fisiologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética
14.
J Immunol ; 186(7): 4306-13, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21357267

RESUMO

Enhanced granulopoietic activity is crucial for host defense against bacterial pneumonia. Alcohol impairs this response. The underlying mechanisms remain obscure. G-CSF produced by infected lung tissue plays a key role in stimulating bone marrow granulopoiesis. This study investigated the effects of alcohol on G-CSF signaling in the regulation of marrow myeloid progenitor cell proliferation in mice with Streptococcus pneumoniae pneumonia. Chronic alcohol consumption plus acute alcohol intoxication suppressed the increase in blood granulocyte counts following intrapulmonary challenge with S. pneumoniae. This suppression was associated with a significant decrease in bone marrow granulopoietic progenitor cell proliferation. Alcohol treatment significantly enhanced STAT3 phosphorylation in bone marrow cells of animals challenged with S. pneumoniae. In vitro experiments showed that G-CSF-induced activation of STAT3-p27(Kip1) pathway in murine myeloid progenitor cell line 32D-G-CSFR cells was markedly enhanced by alcohol exposure. Alcohol dose dependently inhibited G-CSF-stimulated 32D-G-CSFR cell proliferation. This impairment of myeloid progenitor cell proliferation was not attenuated by inhibition of alcohol metabolism through either the alcohol dehydrogenase pathway or the cytochrome P450 system. These data suggest that alcohol enhances G-CSF-associated STAT3-p27(Kip1) signaling, which impairs granulopoietic progenitor cell proliferation by inducing cell cycling arrest and facilitating their terminal differentiation during the granulopoietic response to pulmonary infection.


Assuntos
Regulação para Baixo/imunologia , Etanol/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/fisiologia , Granulócitos/imunologia , Pneumonia Pneumocócica/imunologia , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/imunologia , Regulação para Cima/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/microbiologia , Células da Medula Óssea/patologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p27/fisiologia , Regulação para Baixo/efeitos dos fármacos , Granulócitos/microbiologia , Granulócitos/patologia , Hematopoese/efeitos dos fármacos , Hematopoese/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Pneumocócica/metabolismo , Pneumonia Pneumocócica/patologia , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Streptococcus pneumoniae/imunologia , Regulação para Cima/efeitos dos fármacos
15.
Biomolecules ; 12(7)2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35883501

RESUMO

Effective antiretroviral therapy (ART) has transitioned HIV to a chronic disease, with more than 50% of people living with HIV (PLWH) being over the age of 50. HIV targets activated CD4+ T cells expressing HIV-specific co-receptors (CCR5 and CXCR4). Previously, we reported that chronic binge alcohol (CBA)-administered male rhesus macaques had a higher percentage of gut CD4+ T cells expressing simian immunodeficiency virus (SIV) co-receptor CXCR4. Evidence also suggests that gonadal hormone loss increased activated peripheral T cells. Further, mitochondrial function is critical for HIV replication and alcohol dysregulates mitochondrial homeostasis. Hence, we tested the hypothesis that CBA and ovariectomy (OVX) increase circulating activated CD4+ T cells expressing SIV co-receptors and dysregulate mitochondrial homeostasis in SIV-infected female rhesus macaques. Results showed that at the study end-point, CBA/SHAM animals had increased peripheral CD4+ T cell SIV co-receptor expression, and a lower CD4+ T cell count compared to CBA/OVX animals. CBA and OVX animals had altered peripheral immune cell gene expression important for maintaining mitochondrial homeostasis. These results provide insights into how at-risk alcohol use could potentially impact viral expression in cellular reservoirs, particularly in SIV-infected ovariectomized rhesus macaques.


Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Etanol , Feminino , Expressão Gênica , Homeostase , Hormônios , Humanos , Macaca mulatta , Masculino , Mitocôndrias/metabolismo , Vírus da Imunodeficiência Símia/genética
16.
Front Immunol ; 13: 839390, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634279

RESUMO

CD4+ T cell differentiation to pro-inflammatory and immunosuppressive subsets depends on immunometabolism. Pro-inflammatory CD4+ subsets rely on glycolysis, while immunosuppressive Treg cells require functional mitochondria for their differentiation and function. Previous pre-clinical studies have shown that ethanol (EtOH) administration increases pro-inflammatory CD4+ T cell subsets; whether this shift in immunophenotype is linked to alterations in CD4+ T cell metabolism had not been previously examined. The objective of this study was to determine whether ethanol alters CD4+ immunometabolism, and whether this affects CD4+ T cell differentiation. Naïve human CD4+ T cells were plated on anti-CD3 coated plates with soluble anti-CD28, and differentiated with IL-12 in the presence of ethanol (0 and 50 mM) for 3 days. Both Tbet-expressing (Th1) and FOXP3-expressing (Treg) CD4+ T cells increased after differentiation. Ethanol dysregulated CD4+ T cell differentiation by increasing Th1 and decreasing Treg CD4+ T cell subsets. Ethanol increased glycolysis and impaired oxidative phosphorylation in differentiated CD4+ T cells. Moreover, the glycolytic inhibitor 2-deoxyglucose (2-DG) prevented the ethanol-mediated increase in Tbet-expressing CD4+ T cells but did not attenuate the decrease in FOXP3 expression in differentiated CD4+ T cells. Ethanol increased Treg mitochondrial volume and altered expression of genes implicated in mitophagy and autophagosome formation (PINK1 and ATG7). These results suggest that ethanol impairs CD4+ T cell immunometabolism and disrupts mitochondrial repair processes as it promotes CD4+ T cell differentiation to a pro-inflammatory phenotype.


Assuntos
Linfócitos T CD4-Positivos , Ativação Linfocitária , Diferenciação Celular , Etanol/farmacologia , Fatores de Transcrição Forkhead/metabolismo
17.
Alcohol ; 101: 45-51, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35306109

RESUMO

People living with HIV (PLWH) are at increased risk for noncommunicable diseases such as lung disease in part due to opportunistic infections including pneumonia. HIV infection is associated with increased prevalence of impaired lung function and abnormal gas exchange. Alcohol use disorder (AUD) is exceedingly common in PLWH and is associated with higher risk of pneumonia in PLWH. Alcohol use may lead to lung damage through several mechanisms. Data on the long-term effect of AUD on pulmonary function in PLWH are sparse and conflicting. To evaluate this relationship, we conducted a cross-sectional analysis of adult PLWH in care in Louisiana. We hypothesized that chronic alcohol use would be associated with subsequent pulmonary dysfunction in a dose-dependent fashion. All participants performed standardized spirometry on study entry. In total, 350 participants with acceptable spirometry were included in this analysis. Thirty-one percent of participants were female. Women reported less lifetime alcohol use and less smoking; however, they reported more chronic respiratory symptoms. In adjusted models, total lifetime alcohol use was not associated with spirometry measures of pulmonary function. HIV-related variables (CD4 count and viral load) were also not associated with measures of pulmonary function. We then conducted sex-stratified analyses to eliminate residual confounding of sex and similarly found no association of total lifetime alcohol use and pulmonary function. We found no association of AUDIT score or early life alcohol use and pulmonary function. In latent class factor analysis, current heavy alcohol use was associated with lower measures of pulmonary function as compared to former heavy alcohol use. In summary, in this cohort of New Orleanian men and women living with HIV with robust measures of alcohol use, though total lifetime alcohol use and early life alcohol use were not associated with pulmonary function, current heavy alcohol use was associated with impaired pulmonary function.


Assuntos
Alcoolismo , Infecções por HIV , Pneumopatias , Pneumonia , Adulto , Alcoolismo/epidemiologia , Contagem de Linfócito CD4 , Estudos Transversais , Feminino , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Humanos , Pulmão , Masculino
18.
Crit Care Med ; 39(9): 2121-30, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21602669

RESUMO

OBJECTIVE: Granulocytopenia frequently occurs in alcohol abusers with severe bacterial infection, which strongly correlates with poor clinical outcome. Knowledge of the molecular mechanisms underlying the granulopoietic response to bacterial infection remains limited. This study investigated the involvement of stem cell antigen-1 expression by granulocyte lineage-committed progenitors in the granulopoietic response to septicemia and how alcohol affected this response. DESIGN: : Laboratory investigation. SETTING: University laboratory. SUBJECTS: Male Balb/c mice. INTERVENTIONS: Thirty mins after intraperitoneal injection of alcohol (20% ethanol in saline at 5 g of ethanol/kg) or saline, mice received an intravenous Escherichia coli challenge. MEASUREMENTS AND MAIN RESULTS: E. coli septicemia activated stem cell antigen-1 expression by marrow immature granulocyte differentiation antigen-1 precursors which correlated with an increase in proliferation, granulocyte macrophage colony-forming unit production, and expansion of this granulopoietic precursor cell pool. Acute alcohol treatment suppressed stem cell antigen-1 activation and inhibited the infection-induced increases in proliferation, granulocyte macrophage colony-forming unit production, and expansion the of immature granulocyte differentiation antigen-1 precursor cell population. Consequently, recovery of the marrow mature granulocyte differentiation antigen-1 cell population after E. coli challenge was impaired. Stem cell antigen-1 was induced in sorted granulocyte differentiation antigen-1, stem cell antigen-1' cells by lipopolysaccharide-stimulated C-Jun kinase activation that was also inhibited by alcohol. Furthermore, stem cell antigen-1 knockout mice failed to expand the marrow immature granulocyte differentiation antigen-1 cell pool and demonstrated fewer newly produced granulocytes in the circulation after the E. coli challenge. CONCLUSIONS: Alcohol suppresses the stem cell antigen-1 response in granulocyte lineage-committed precursors and restricts granulocyte production during septicemia, which may serve as a novel mechanism underlying impaired host defense in alcohol abusers.


Assuntos
Agranulocitose/induzido quimicamente , Antígenos Ly/fisiologia , Etanol/farmacologia , Proteínas de Membrana/fisiologia , Sepse/imunologia , Agranulocitose/metabolismo , Agranulocitose/fisiopatologia , Animais , Western Blotting , Células da Medula Óssea/fisiologia , Infecções por Escherichia coli/imunologia , Citometria de Fluxo , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Masculino , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C
19.
J Immunol ; 182(3): 1568-76, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19155505

RESUMO

Alcohol abuse predisposes the host to bacterial infections. In response to bacterial infection, the bone marrow hematopoietic activity shifts toward granulocyte production, which is critical for enhancing host defense. This study investigated the hematopoietic precursor cell response to bacteremia and how alcohol affects this response. Acute alcohol intoxication was induced in BALB/c mice 30 min before initiation of Escherichia coli bacteremia. Bacteremia caused a significant increase in the number of bone marrow lineage (lin(-))-c-kit(+)Sca-1(+) cells. Marrow lin(-)c-kit(+)Sca-1(+) cells isolated from bacteremic mice showed an increase in CFU-granulocyte/macrophage activity compared with controls. In addition to enhanced proliferation of lin(-)c-kit(+)Sca-1(+) cells as reflected by BrdU incorporation, phenotypic inversion of lin(-)c-kit(+)Sca-1(+)Sca-1(-) cells primarily accounted for the rapid increase in marrow lin(-)c-kit(+)Sca-1(+) cells following bacteremia. Bacteremia increased plasma concentration of TNF-alpha. Culture of marrow lin(-)c-kit(+)Sca-1(+)Sca-1(-) cells with murine rTNF-alpha for 24 h caused a dose-dependent increase in conversion of these cells to lin(-)c-kit(+)Sca-1(+) cells. Sca-1 mRNA expression by the cultured cells was also up-regulated following TNF-alpha stimulation. Acute alcohol intoxication inhibited the increase in the number of lin(-)c-kit(+)Sca-1(+) cells in the bone marrow after E. coli infection. Alcohol impeded the increase in BrdU incorporation into marrow lin(-)c-kit(+)Sca-1(+) cells in response to bacteremia. Alcohol also suppressed the plasma TNF-alpha response to bacteremia and inhibited TNF-alpha-induced phenotypic inversion of lin(-)c-kit(+)Sca-1(+)Sca-1(-) cells in vitro. These data show that alcohol inhibits the hematopoietic precursor cell response to bacteremia, which may serve as one mechanism underlying the impaired host defense in alcohol abusers with severe bacterial infections.


Assuntos
Intoxicação Alcoólica/imunologia , Bacteriemia/imunologia , Linhagem da Célula/imunologia , Infecções por Escherichia coli/imunologia , Células-Tronco Hematopoéticas/imunologia , Terapia de Imunossupressão , Proteínas de Membrana/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/metabolismo , Intoxicação Alcoólica/microbiologia , Intoxicação Alcoólica/patologia , Animais , Antígenos Ly/biossíntese , Antígenos Ly/fisiologia , Bacteriemia/microbiologia , Bacteriemia/patologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Técnicas de Cultura de Células , Diferenciação Celular/imunologia , Citocinas/sangue , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Imunofenotipagem , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-kit/biossíntese
20.
Proc Natl Acad Sci U S A ; 105(5): 1668-73, 2008 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-18216245

RESUMO

Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1alpha, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.


Assuntos
Vasos Coronários/fisiologia , Mioblastos Cardíacos/fisiologia , Neovascularização Fisiológica , Regeneração , Células-Tronco/fisiologia , Animais , Diferenciação Celular , Quimiocina CXCL12/metabolismo , Vasos Coronários/citologia , Células Endoteliais/citologia , Feminino , Fator de Crescimento de Hepatócito/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/transplante , Isquemia Miocárdica/metabolismo , Miócitos de Músculo Liso/citologia , Proteínas Proto-Oncogênicas c-kit/análise , Ratos , Ratos Endogâmicos F344 , Transplante de Células-Tronco , Células-Tronco/química , Células-Tronco/efeitos dos fármacos
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