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1.
Methods Mol Biol ; 2041: 345-349, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646502

RESUMO

Extracellular nucleotides are potent damage-associated molecular patterns that shape the immune response to cell stress and tissue damage. These nucleotides are sensed by purinergic receptors and mediate a wide range of cellular effects. Among the best characterized of these effects is cellular migration. While the motility responses of leukocytes to nucleotides can be achieved by microscopic live-cell imaging approaches, such systems are time-consuming and require costly equipment and analysis tools not readily available to all researchers. Transwell migration chambers are a widely used alternative to microscopy due to their relatively low cost and moderate through-put capacity. However, extracellular nucleotides are labile and rapidly degraded in serum-containing cell cultures due to the presence of phosphohydrolases. Thus, evaluating leukocyte migration to nucleotides presents a number of challenges not seen with more stable classes of chemoattractants like proteins and lipids. Here we describe a method to measure leukocyte migration to nucleotides that is cost-effective, rapid and produces robust and reproducible migration of leukocytes using transwell migration chambers.

2.
Menopause ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31567864

RESUMO

OBJECTIVE: Although reproductive function is influenced by season, few studies have evaluated seasonal effects on menopausal symptoms. We assessed the impact of season and proximity to the final menstrual period (FMP) on frequency of symptom reporting. METHODS: In all, 955 participants in the Study of Women's Health Across the Nation recorded whether or not they had experienced menopausal symptoms on a monthly menstrual calendar over a 10-year period. We modeled the log-odds of presence of a given symptom each month using a logistic mixed-effects model, assuming a third-order polynomial before the FMP and a different third-order polynomial after the FMP. We assumed sine and cosine functions for month of the year. RESULTS: Five to 10 years before the FMP, ∼20% of women reported hot flashes and night sweats, whereas ∼40% reported trouble sleeping. Prevalence rose ∼4 years before the FMP with a sharp jump in hot flash (∼60%) and night sweats (∼40%) prevalence coincident with the FMP. Peaks in hot flashes and trouble sleeping were observed in July with troughs in January. The peak and trough in night sweats occurred about 1 month earlier. Odds of hot flashes, night sweats, and trouble sleeping were 66%, 50%, and 24% greater, respectively, at the seasonal peak versus the seasonal minimum. CONCLUSION: Menopausal symptoms exhibit seasonal variation associated with the summer and winter equinoxes. Seasonal increases in night sweats precede increases in hot flashes. Prospectively recorded monthly symptom data demonstrate that hot flashes and night sweats increase notably coincident with the FMP. : Video Summary:http://links.lww.com/MENO/A476.

3.
Infect Immun ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31611280

RESUMO

The pulmonary immune response protects healthy individuals against Pneumocystis pneumonia (PcP). However, the immune response also drives immunopathogenesis in patients who develop severe PcP, and it is generally accepted that optimal treatment will require combination strategies that promote fungal killing and provide effective immunomodulation. The anti-inflammatory drug sulfasalazine programs macrophages for enhanced Pneumocystis phagocytosis and also suppresses PcP-related immunopathogenesis. Anti-Pc antibody opsonizes Pneumocystis organisms for greater phagocytosis and may also mask antigens that drive immunopathogenesis. Thus, we hypothesized that combining antibody and sulfasalazine would have the dual benefit of enhancing fungal clearance while dampening immunopathogenesis, and allow the rescue of severe PcP. To model a clinically relevant treatment scenario in mice, therapeutic interventions were withheld until clear symptoms of pneumonia were evident. When administered individually, both passive antibody and sulfasalazine improved pulmonary function and enhanced Pneumocystis clearance to a similar degree. However, combination treatment with antibody and sulfasalazine produced a more rapid improvement, with recovery of body weight, dramatic improvement in pulmonary function, reduced lung inflammation, and rapid clearance of Pneumocystis Accelerated fungal clearance in the combination treatment group was associated with a significant increase in macrophage phagocytosis of Pneumocystis Both passive antibody and sulfasalazine resulted in suppression of Th1 cytokines and a marked increase in lung macrophages displaying an alternatively activated phenotype, which was enhanced by combination treatment. Our data support the concept that passive antibody and sulfasalazine could be an effective and specific adjunctive therapy for PcP, with the potential to accelerate fungal clearance while attenuating PcP-associated immunopathogenesis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31480698

RESUMO

(1) Background: Smoking restrictions have been shown to be associated with reduced smoking, but there are a number of gaps in the literature surrounding the relationship between smoke-free policies and cessation, including the extent to which this association may be modified by sociodemographic characteristics. (2) Methods: We analyzed data from the Tobacco Use Supplement to the Current Population Survey, 2003-2015, to explore whether multiple measures of smoking restrictions were associated with cessation across population subgroups. We examined area-based measures of exposure to smoke-free laws, as well as self-reported exposure to workplace smoke-free policies. We used age-stratified, fixed effects logistic regression models to assess the impact of each smoke-free measure on 90-day cessation. Effect modification by gender, education, family income, and race/ethnicity was examined using interaction terms. (3) Results: Coverage by workplace smoke-free laws and self-reported workplace smoke-free policies was associated with higher odds of cessation among respondents ages 40-54. Family income modified the association between smoke-free workplace laws and cessation for women ages 25-39 (the change in the probability of cessation associated with coverage was most pronounced among lower-income women). (4) Conclusions: Heterogeneous associations between policies and cessation suggest that smoke-free policies may have important implications for health equity.

5.
Stroke ; 50(11): 3191-3197, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31526122

RESUMO

Background and Purpose- Stroke is the leading cause of serious, long-term disability in the United States, and the number of stroke survivors is projected to rise. Physical functioning status may be compromised in survivors living in low socioeconomic status environments in comparison to higher socioeconomic status environments. Higher socioeconomic status environments may include benefits in the built environment such as sidewalks, accessible transit, or low traffic volume. Investigation is needed to understand the effects of the socioenvironmental context on trajectories of stroke survivors' physical health-related quality of life (PH-QOL) over time. Methods- Participants from the REGARDS (REasons for Geographic and Racial Differences in Stroke) study enrolled in the ancillary Caring for Adults Recovering from the Effects of Stroke project completed the SF-12 around 6 to 12, 18, 27, and 36 months poststroke. Measures of area-level income, wealth, education, and employment at the census tract level were combined to represent participants' neighborhood socioeconomic status. Linear mixed models were used to predict trajectories of PH-QOL over time, controlling for individual characteristics. Results- The average trajectory of PH-QOL was flat over time. However, women and younger stroke survivors had better trajectories over time than men and older stroke survivors. Higher neighborhood socioeconomic status was significantly associated with better PH-QOL across all time points (ß=1.73; 95% CI, 0.17-3.30), after controlling for demographic variables and severity of stroke. Conclusions- Our findings demonstrate that neighborhood socioeconomic status, sex, and age are associated with the poststroke recovery process. The results of this study suggest the importance of evaluating the environment surrounding stroke survivors when they return to their home communities. Future research should identify specific features of the environment within different socioeconomic status neighborhoods to better understand how they contribute to PH-QOL among stroke survivors.

6.
7.
ANZ J Surg ; 89(7-8): 795, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31379079
8.
Muscle Nerve ; 60(5): 513-519, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31397910

RESUMO

BACKGROUND: Our pilot study tested the feasibility and performance of an eye-controlled power wheelchair for amyotrophic lateral sclerosis (ALS) patients. METHODS: In this prospective pilot study, participants drove the wheelchair three times around an indoor course. We assessed the time to complete the course; starting and stopping on command; turning 90, 135, and 180 degrees; time to backup; and obstacle negotiation. Following their use of the wheelchair, subjects were given a questionnaire to assess user experience. RESULTS: Twelve patients participated, and all were able to complete three trials without difficulty. Eight participants completed all of the individual tasks (eg, turning, stopping, etc.) without any errors. Overall performance ratings were high across all participants (4.6/5-excellent). CONCLUSIONS: Our eye-controlled power wheelchair prototype is feasible and has a very favorable user experience. This system has the potential to improve the mobility and independence of ALS patients, and other groups with motor impairments.

10.
PLoS One ; 14(7): e0219301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291324

RESUMO

BACKGROUND: The potential impacts of beverage intake during the midlife on future subclinical atherosclerosis among women are unclear. The aim of this study was to evaluate the prospective associations between the intakes of eight beverage groups and subclinical carotid atherosclerosis in midlife women. METHODS: Data came from the Study of Women's Health Across the Nation, a multicenter, multiethnic, and prospective cohort study. A total of 1,235 midlife women had measures of subclinical carotid atherosclerosis and repeatedly beverage intake data collected using a validated food frequency questionnaire. Beverages were aggregated into eight groups, including coffee, tea, sugar-sweetened beverages, artificially sweetened beverages, fruit juices, whole milk, milk with lower fat content, and alcoholic beverages. The associations of beverage intake with common carotid artery intima-media thickness (CCA-IMT) and adventitial diameter (CCA-AD) were estimated using linear models; the associations with carotid plaque were estimated using log-binomial models. RESULTS: Coffee intake was associated with CCA-IMT in an inverted J-shaped pattern. After adjusting for covariates, women with >0 to <1 cup/day and 1 to <2 cups/day of coffee intake had a 0.031 mm (95% CI: 0.012, 0.051) and a 0.027 mm (95% CI: 0.005, 0.049) larger CCA-IMT, respectively, than coffee non-drinkers. Women who consumed ≥2 cups/day of coffee did not have significantly different CCA-IMT than non-drinkers. There was an inverse linear association between moderate alcoholic beverages intake and CCA-IMT (P-trend = 0.014). Whole milk intake had inverted U-shaped associations with CCA-IMT and carotid plaque. No significant associations were found between other beverage groups and subclinical atherosclerosis. CONCLUSIONS: In midlife women, occasional coffee intake may be associated with more subclinical atherosclerosis while moderate alcoholic beverages intake may be associated with less subclinical atherosclerosis. Future work should focus on the determination of the optimal beverage intake profile for maximum cardiovascular benefits in midlife women.

11.
J Epidemiol Glob Health ; 9(2): 103-106, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31241867

RESUMO

Depression is a leading cause of disability worldwide and can be diagnosed and treated in primary care clinics. No studies to date have demonstrated the prevalence of depression in rural, primary care settings in Mexico. The objective of this study is to describe the prevalence of visits for depression in primary care settings in one group of rural communities within Chiapas, Mexico. We performed a cross-sectional, retrospective study of depression prevalence in primary care clinics in the Sierra region of Chiapas, Mexico during the calendar year of 2014. We determined the average depression prevalence is 7.9% (6 community clinics, n = 4555). The prevalence of depression in rural Chiapas, Mexico is much higher than the Mexican national average of 4.0-4.5% found in a home-based survey. Further efforts to understand the causes, develop improved mental health services in primary care, and reduce the higher burden of depression in rural communities in Mexico are urgently needed.

12.
Epidemiology ; 30(4): 597-608, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31045611

RESUMO

BACKGROUND: The All of Us Research Program is building a national longitudinal cohort and collecting data from multiple information sources (e.g., biospecimens, electronic health records, and mobile/wearable technologies) to advance precision medicine. Participant-provided information, collected via surveys, will complement and augment these information sources. We report the process used to develop and refine the initial three surveys for this program. METHODS: The All of Us survey development process included: (1) prioritization of domains for scientific needs, (2) examination of existing validated instruments, (3) content creation, (4) evaluation and refinement via cognitive interviews and online testing, (5) content review by key stakeholders, and (6) launch in the All of Us electronic participant portal. All content was translated into Spanish. RESULTS: We conducted cognitive interviews in English and Spanish with 169 participants, and 573 individuals completed online testing. Feedback led to over 40 item content changes. Lessons learned included: (1) validated survey instruments performed well in diverse populations reflective of All of Us; (2) parallel evaluation of multiple languages can ensure optimal survey deployment; (3) recruitment challenges in diverse populations required multiple strategies; and (4) key stakeholders improved integration of surveys into larger Program context. CONCLUSIONS: This efficient, iterative process led to successful testing, refinement, and launch of three All of Us surveys. Reuse of All of Us surveys, available at http://researchallofus.org, may facilitate large consortia targeting diverse populations in English and Spanish to capture participant-provided information to supplement other data, such as genetic, physical measurements, or data from electronic health records.

13.
Mol Neurobiol ; 56(10): 7188-7207, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30997640

RESUMO

Sphingosine-1-phosphate (S1P) produced by sphingosine kinases (SPHK1 and SPHK2) is a signaling molecule involved in cell proliferation and formation of cellular junctions. In this study, we characterized the retinas of Sphk1 knockout (KO) mice by electron microscopy and immunocytochemistry. We also tested cultured Müller glia for their response to S1P. We found that S1P plays an important role in retinal and retinal pigment epithelial (RPE) structural integrity in aging mice. Ultrastructural analysis of Sphk1 KO mouse retinas aged to 15 months or raised with moderate light stress revealed a degenerated outer limiting membrane (OLM). This membrane is formed by adherens junctions between neighboring Müller glia and photoreceptor cells. We also show that Sphk1 KO mice have reduced retinal function in mice raised with moderate light stress. In vitro assays revealed that exogenous S1P modulated cytoskeletal rearrangement and increased N-cadherin production in human Müller glia cells. Aged mice also had morphological degeneration of the RPE, as well as increased lipid storage vacuoles and undigested phagosomes reminiscent of RPE in age-related macular degeneration. These findings show that SPHK1 and S1P play a vital role in the structural maintenance of the mammalian retina and retinal pigmented epithelium by supporting the formation of adherens junctions.

14.
JCI Insight ; 52019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30998506

RESUMO

The bone marrow microenvironment (BMME) contributes to the regulation of hematopoietic stem cell (HSC) function, though its role in age-associated lineage skewing is poorly understood. Here we show that dysfunction of aged marrow macrophages (Mφs) directs HSC platelet-bias. Mφs from the marrow of aged mice and humans exhibited an activated phenotype, with increased expression of inflammatory signals. Aged marrow Mφs also displayed decreased phagocytic function. Senescent neutrophils, typically cleared by marrow Mφs, were markedly increased in aged mice, consistent with functional defects in Mφ phagocytosis and efferocytosis. In aged mice, Interleukin 1B (IL1B) was elevated in the bone marrow and caspase 1 activity, which can process pro-IL1B, was increased in marrow Mφs and neutrophils. Mechanistically, IL1B signaling was necessary and sufficient to induce a platelet bias in HSCs. In young mice, depletion of phagocytic cell populations or loss of the efferocytic receptor Axl expanded platelet-biased HSCs. Our data support a model wherein increased inflammatory signals and decreased phagocytic function of aged marrow Mφs induce the acquisition of platelet bias in aged HSCs. This work highlights the instructive role of Mφs and IL1B in the age-associated lineage-skewing of HSCs, and reveals the therapeutic potential of their manipulation as antigeronic targets.

15.
Diabetes Care ; 42(7): 1290-1296, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31010876

RESUMO

OBJECTIVE: To determine the prevalence and prognostic significance of unrecognized myocardial infarction (MI) by delayed-enhancement MRI (DE-MRI) in asymptomatic patients with diabetes. RESEARCH DESIGN AND METHODS: In this prospective, two-center study of asymptomatic patients without known cardiac disease (n = 120), two prespecified cohorts underwent a research MRI: 1) a high-risk group with type 1 diabetes and chronic renal insufficiency (n = 50) and 2) an average-risk group with type 2 diabetes (n = 70). The primary end point was a composite of all-cause mortality and clinical MI. RESULTS: Overall, the prevalence of unrecognized MI was 19% by DE-MRI (28% high-risk group and 13% average-risk group) and 5% by electrocardiography. During up to 5 years of follow-up with a total of 460 patient-years of follow-up, the rate of death/MI was markedly higher in patients with diabetes with (vs. without) unrecognized MI (all 44% vs. 7%, high-risk group 43% vs. 6%, and average-risk group 44% vs. 8%; all P < 0.01). After adjustment for Framingham risk score, left ventricular ejection fraction, and diabetes type, the presence of unrecognized MI by DE-MRI conferred an eightfold increase in risk of death/MI (95% CI 3.0-21.1, P < 0.0001). Addition of unrecognized MI to clinical indices significantly improved model discrimination for adverse events (integrated discrimination improvement = 0.156, P = 0.001). CONCLUSIONS: Unrecognized MI is prevalent in asymptomatic patients with diabetes without a history of cardiac disease and confers a markedly increased risk of death and clinical MI.

16.
J Pediatr Orthop ; 39(4): e289-e292, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30839480

RESUMO

BACKGROUND: Magnetic growing rods are being utilized more frequently in children with early-onset scoliosis. Many of these children have multiple medical problems and additional medical devices implanted that utilize similar magnetic technology, including vagal nerve stimulator (VNS) devices. There is some concern that the external remote controller (ERC) used to control the magnetic growth rod will interact with these devices during lengthening procedures. We believe there are safe parameters which allow the magnetic growth rod ERC to be utilized in patients with an implanted VNS. METHODS: A VNS device was tested in a simulation with the magnetic growth rods ERC to determine if it would activate/inactivate the device during a lengthening procedure. This study consists of 2 simulations. Simulation 1 evaluates placing the VNS adjacent to the ERC in the same coronal plane. Simulation 2 elevates the ERC placement above the device to simulate the thickness of a torso while increasing the distance of the VNS from the ERC in the coronal plane. RESULTS: The time of exposure of the VNS device to the magnetic field had no correlation with activation. Distance had an effect on device activation. In the coronal plane of the device, activation occurred 43% of the time at 0 cm, 71% at 4 cm, and 5% activation at 8 cm. Greater than 10 cm had no activation. In the sagittal plane with the ERC 8 cm above the device, activation occurred 71% at 0 cm distance, 38% at 2 cm, and no activation occurred at a distance of >4 cm. CONCLUSIONS: Utilization of the magnetic growth rod ERC can be carried out safely in patients with a VNS. Simulations show that an actuator implanted 4 cm from the VNS device in the coronal plane in a child with >8 cm chest wall thickness will not activate the VNS device. When choosing a rod configuration for implantation, the child's chest wall thickness and the ERC placement should be considered.


Assuntos
Imãs , Próteses e Implantes , Escoliose/terapia , Estimulação do Nervo Vago , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Escoliose/diagnóstico por imagem , Escoliose/cirurgia
17.
JCI Insight ; 4(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30702442

RESUMO

ß-2 Microglobulin (ß2M) is a molecular chaperone for the major histocompatibility class I (MHC I) complex, hemochromatosis factor protein (HFE), and the neonatal Fc receptor (FcRn), but ß2M may also have less understood chaperone-independent functions. Elevated plasma ß2M has a direct role in neurocognitive decline and is a risk factor for adverse cardiovascular events. ß2M mRNA is present in platelets at very high levels, and ß2M is part of the activated platelet releasate. In addition to their more well-studied thrombotic functions, platelets are important immune regulatory cells that release inflammatory molecules and contribute to leukocyte trafficking, activation, and differentiation. We have now found that platelet-derived ß2M is a mediator of monocyte proinflammatory differentiation through noncanonical TGFß receptor signaling. Circulating monocytes from mice lacking ß2M only in platelets (Plt-ß2M-/-) had a more proreparative monocyte phenotype, in part dependent on increased platelet-derived TGFß signaling in the absence of ß2M. Using a mouse myocardial infarction (MI) model, Plt-ß2M-/- mice had limited post-MI proinflammatory monocyte responses and, instead, demonstrated early proreparative monocyte differentiation, profibrotic myofibroblast responses, and a rapid decline in heart function compared with WT mice. These data demonstrate a potentially novel chaperone-independent, monocyte phenotype-regulatory function for platelet ß2M and that platelet-derived 2M and TGFß have opposing roles in monocyte differentiation that may be important in tissue injury responses.

18.
Pediatrics ; 143(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718381

RESUMO

: media-1vid110.1542/5984244682001PEDS-VA_2018-2507Video Abstract BACKGROUND AND OBJECTIVE: Unrestrained child passengers are at significant risk of crash-related injury. Previous researchers using nationally representative crash data from 1992 to 1993 found an association between driver and passenger safety-belt use. Our objective in this study is to investigate factors associated with young, unrestrained passengers in fatal and nonfatal motor vehicle crashes using updated national crash data. METHODS: We analyzed 2011-2015 Fatality Analysis Reporting System and National Automotive Sampling System data and included vehicles with a young passenger (≤19 years old) in a crash. Driver and passenger characteristics were compared by using bivariate analyses separately for fatal and nonfatal crashes. Logistic regression analyses were performed on a combined data set to predict passenger restraint use. RESULTS: In unadjusted bivariate models, unrestrained drivers had a higher probability of having an unrestrained passenger across all passenger age groups for both fatal and nonfatal crashes. In multivariate logistic regression models that included both fatal and nonfatal crashes and were adjusted for several driver and passenger characteristics, unrestrained drivers had a higher risk of having an unrestrained young passenger across all age groups. CONCLUSIONS: In both fatal and nonfatal crashes, a driver being unrestrained is a strong predictor of the child passenger also being unrestrained. Policy and regulation to better ensure that drivers are properly restrained (eg, expanding primary seat-belt laws to all states) may serve as effective means for increasing rates of proper child-occupant-restraint use.


Assuntos
Acidentes de Trânsito/mortalidade , Cintos de Segurança , Acidentes de Trânsito/tendências , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Cintos de Segurança/tendências , Adulto Jovem
19.
Nat Immunol ; 20(5): 613-625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30778243

RESUMO

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8+ T cells confer cross-protection against IAV strains, however the responses of CD8+ T cells to IBV and ICV are understudied. We investigated the breadth of CD8+ T cell cross-recognition and provide evidence of CD8+ T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8+ T cell epitopes from IBVs that were protective in mice and found memory CD8+ T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8+ T cells displayed tissue-resident memory phenotypes. Notably, CD38+Ki67+CD8+ effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8+ T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas/imunologia , Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Influenza Humana/imunologia , Influenzavirus C/imunologia , Adolescente , Adulto , Idoso , Animais , Linfócitos T CD8-Positivos/virologia , Criança , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Vírus da Influenza A/fisiologia , Vírus da Influenza B/fisiologia , Vacinas contra Influenza/imunologia , Influenza Humana/virologia , Influenzavirus C/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
20.
Nat Immunol ; 20(2): 141-151, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643265

RESUMO

Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population. We noted single-nucleotide polymorphisms (SNPs) in the apoptotic cell-engulfment genes ELMO1, DOCK2, and RAC1 linked to rheumatoid arthritis. As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis. Surprisingly, Elmo1-deficient mice showed reduced joint inflammation in acute and chronic arthritis models. Genetic and cell-biology studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses. Further, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to chemokines linked to arthritis. These data identify 'noncanonical' roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Neutrófilos/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/imunologia , Artrite Experimental/diagnóstico , Artrite Experimental/genética , Artrite Experimental/patologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Quimiotaxia/genética , Quimiotaxia/imunologia , Colágeno/imunologia , Complemento C5a/imunologia , Complemento C5a/metabolismo , Citoplasma/imunologia , Citoplasma/metabolismo , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Microscopia Intravital , Articulações/citologia , Articulações/imunologia , Leucotrieno B4/imunologia , Leucotrieno B4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/metabolismo , Polimorfismo de Nucleotídeo Único , Proteômica , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Imagem com Lapso de Tempo
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