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1.
Community Health Equity Res Policy ; : 2752535X231205665, 2023 Oct 14.
Article in English | MEDLINE | ID: mdl-37837451

ABSTRACT

BACKGROUND: Influenza (flu) and COVID-19 vaccination rates are subpar across the US, especially in racial and/or socioeconomic minority groups who are understudied in public health literature. OBJECTIVE: The objective of this mixed-methods study was to elucidate attitudes of patients at the Turtle Creek Primary Care Center, a clinic that cares for ∼70% non-white patients, towards flu and COVID-19 vaccines, with the goal of establishing vaccine education gaps and increasing vaccine uptake in minority communities. DESIGN/PATIENTS: This study was conducted as a cross-sectional analysis. Authors completed 123 patient phone surveys of patients cared for at the Turtle Creek clinic inquiring about flu and COVID-19 infection status and vaccination uptake (August 26-October 10, 2021). APPROACH/KEY RESULTS: We found that rates of vaccination were subpar in the Turtle Creek community, with only 54% having received the COVID-19 vaccine and only 44% receiving the flu vaccine regularly. There was a strong association between COVID-19 and flu vaccine acceptance and a notable correlation between vaccine acceptance and age. When assessing how vaccine acceptance was influenced by trusted sources of information, those who cited trusting "medical professionals" and "word of mouth" had higher odds of COVID-19 vaccine acceptance but those who cited trusting "social media" had decreased odds of acceptance. Finally, we uncovered 14 common factors for either vaccine acceptance or refusal that clustered into four overarching themes of trust, need, safety, and availability. CONCLUSION: These data highlight the necessity of improved vaccine education and reveal targetable populations and approaches for disseminating vaccine information.

2.
J Biol Chem ; 298(6): 101926, 2022 06.
Article in English | MEDLINE | ID: mdl-35413288

ABSTRACT

Skeletal muscle dynamically regulates systemic nutrient homeostasis through transcriptional adaptations to physiological cues. In response to changes in the metabolic environment (e.g., alterations in circulating glucose or lipid levels), networks of transcription factors and coregulators are recruited to specific genomic loci to fine-tune homeostatic gene regulation. Elucidating these mechanisms is of particular interest as these gene regulatory pathways can serve as potential targets to treat metabolic disease. The zinc-finger transcription factor Krüppel-like factor 15 (KLF15) is a critical regulator of metabolic homeostasis; however, its genome-wide distribution in skeletal muscle has not been previously identified. Here, we characterize the KLF15 cistrome in vivo in skeletal muscle and find that the majority of KLF15 binding is localized to distal intergenic regions and associated with genes related to circadian rhythmicity and lipid metabolism. We also identify critical interdependence between KLF15 and the nuclear receptor PPARδ in the regulation of lipid metabolic gene programs. We further demonstrate that KLF15 and PPARδ colocalize genome-wide, physically interact, and are dependent on one another to exert their transcriptional effects on target genes. These findings reveal that skeletal muscle KLF15 plays a critical role in metabolic adaptation through its direct actions on target genes and interactions with other nodal transcription factors such as PPARδ.


Subject(s)
Kruppel-Like Transcription Factors , Lipid Metabolism , Muscle, Skeletal , PPAR delta , Animals , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Lipid Metabolism/genetics , Mice , Muscle, Skeletal/metabolism , PPAR delta/genetics , PPAR delta/metabolism
3.
Exp Gerontol ; 163: 111776, 2022 06 15.
Article in English | MEDLINE | ID: mdl-35339632

ABSTRACT

BACKGROUND: Mobility is important for independence in older age. While brain health correlates of objectively measured mobility-related features like gait and balance have been reported, we aimed to test neuroimaging and cognitive correlates of subjective measures of mobility-related confidence. METHODS: We carried out a cross-sectional observational study comprised of N = 29 cognitively unimpaired older adult participants, mean age 75.8 ± 5.8, 52% female, 24% non-white. We measured cognition, hippocampal volume, white matter hyperintensities, cerebral amyloid-ß (Aß), and gait and balance confidence. We tested associations using unadjusted Spearman correlations and correlations partialling out covariates of interest one at a time. RESULTS: Greater gait confidence was associated with better attention (unadjusted ρ = 0.37, p = 0.05; partially attenuated by adjustment for age, APOE4, anxiety, motivation, gait speed, or Aß); executive performance (unadjusted ρ = 0.35, p = 0.06; partially attenuated by adjustment for age, APOE4, gait speed, or Aß); and lower Aß levels (unadjusted ρ = -0.40, p = 0.04; partially attenuated by adjustment for age, depressive symptoms, motivation, or gait speed). Greater balance confidence was associated with better global cognition (unadjusted ρ = 0.41, p = 0.03; partially attenuated by adjustment for APOE4, gait speed, or Aß); attention (unadjusted ρ = 0.46, p = 0.01; robust to adjustment); and lower Aß levels (unadjusted ρ = -0.35, p = 0.07; partially attenuated by adjustment for age, education, APOE4, depressive symptoms, anxiety, motivation, or gait speed). CONCLUSIONS: Self-reported mobility-related confidence is associated with neuroimaging and cognitive measures and would be easy for providers to use in clinical evaluations. These associations should be further evaluated in larger samples, and longitudinal studies can help determine temporality of declines.


Subject(s)
Apolipoprotein E4 , Brain , Aged , Aged, 80 and over , Amyloid beta-Peptides/metabolism , Brain/diagnostic imaging , Brain/metabolism , Cross-Sectional Studies , Female , Gait , Humans , Male , Risk Factors
4.
Shock ; 55(3): 338-348, 2021 03 01.
Article in English | MEDLINE | ID: mdl-32925605

ABSTRACT

ABSTRACT: Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. Cell necroptosis features receptor-interacting protein (RIPK) 1 activation and necroptosome formation. This leads to loss of plasma membrane integrity, the release of cell contents into the extracellular space, and subsequent increased inflammation. Here, we report an intra-PMN mechanism of negative regulation of necroptosis mediated through TBK1/IKKε. Using an in vivo mouse model of intratracheal injection (i.t.) of LPS and in vitro LPS stimulation of mouse PMN, we found that LPS-TLR4 signaling in PMNs activates and phosphorylates TBK1 and IKKε, which in turn suppress LPS-induced formation of the RIPK1-RIPK3-MLKL (necrosome) complex. TBK1 dysfunction by knockdown or inhibitor significantly increases the phosphorylation of RIPK1 (∼67%), RIPK3 (∼68%), and MLKL (∼50%) and promotes RIPK1-RIPK3 and RIPK3-MLKL interactions and increases PMN necroptosis (∼83%) in response to LPS, with subsequent augmented lung inflammation. These findings suggest that the LPS-TLR4-TBK1 axis serves as a negative regulator for PMN necroptosis and might be a therapeutic target for modulating PMN death and inflammation.


Subject(s)
I-kappa B Kinase/physiology , Necroptosis/physiology , Neutrophils/physiology , Protein Serine-Threonine Kinases/physiology , Animals , Lipopolysaccharides/administration & dosage , Male , Mice , Mice, Inbred C57BL , Pneumonia
5.
Shock ; 55(2): 167-176, 2021 02 01.
Article in English | MEDLINE | ID: mdl-32694389

ABSTRACT

ABSTRACT: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are caused by an exaggerated inflammatory response arising from a wide variety of pulmonary and systemic insults. Lung tissue is composed of a variety of cell populations, including parenchymal and immune cells. Emerging evidence has revealed that multiple cell populations in the lung work in concert to regulate lung inflammation in response to both direct and indirect stimulations. To date, the question of how different types of pulmonary cells communicate with each other and subsequently regulate or modulate inflammatory cascades remains to be fully addressed. In this review, we provide an overview of current advancements in understanding the role of cell-cell interaction in the development of ALI and depict molecular mechanisms by which cell-cell interactions regulate lung inflammation, focusing on inter-cellular activities and signaling pathways that point to possible therapeutic opportunities for ALI/ARDS.


Subject(s)
Acute Lung Injury/physiopathology , Cell Communication , Neutrophils/physiology , Respiratory Distress Syndrome/physiopathology , Humans
6.
Protein Cell ; 11(8): 618-619, 2020 08.
Article in English | MEDLINE | ID: mdl-32125673

ABSTRACT

In the original publication the bands in Fig. 1J and Fig. 2B were not visible. The correct versions of Fig. 1J and Fig. 2B are provided in this correction.

8.
Respir Res ; 19(1): 50, 2018 03 27.
Article in English | MEDLINE | ID: mdl-29587748

ABSTRACT

Acute lung injury (ALI) and its severe form, known as acute respiratory distress syndrome (ARDS), are caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis, trauma, and major surgery. The reciprocal influences between pulmonary and systemic inflammation augments the inflammatory process in the lung and promotes the development of ALI. Emerging evidence has revealed that alveolar macrophage (AM) death plays important roles in the progression of lung inflammation through its influence on other immune cell populations in the lung. Cell death and tissue inflammation form a positive feedback cycle, ultimately leading to exaggerated inflammation and development of disease. Pharmacological manipulation of AM death signals may serve as a logical therapeutic strategy for ALI/ARDS. This review will focus on recent advances in the regulation and underlying mechanisms of AM death as well as the influence of AM death on the development of ALI.


Subject(s)
Acute Lung Injury/metabolism , Cell Death/physiology , Macrophages, Alveolar/metabolism , Respiratory Distress Syndrome/metabolism , Acute Lung Injury/pathology , Animals , Humans , Macrophages, Alveolar/pathology , Pneumonia/metabolism , Pneumonia/pathology , Respiratory Distress Syndrome/pathology , Signal Transduction/physiology
9.
Cell Death Dis ; 9(3): 369, 2018 03 06.
Article in English | MEDLINE | ID: mdl-29511181

ABSTRACT

Group 2 innate lymphoid cells (ILC2) are one of three subgroups of innate lymphoid cells (ILC1, ILC2, and ILC3), and the major ILC population detected in the lungs. The function of ILC2 in the regulation of lung inflammation remains unclear. In the current study, we explored an important role of ILC2 in protecting lung endothelial cell (EC) from pyroptosis in sepsis-induced acute lung inflammation and the underlying mechanism. Using a cecal ligation and puncture (CLP) mouse sepsis model, we demonstrated that IL-33, which is released in response to sepsis, acting through its receptor ST2 mediates ILC2 expansion in the lungs. We further showed that the increased ILC2 in the lungs secrete IL-9, which in turn prevents lung EC from undergoing pyroptosis, a pro-inflammatory cell death form, by attenuating caspase-1 activation. These findings suggest a previously unidentified innate pathway that negatively regulates lung inflammation following sepsis.


Subject(s)
Endothelial Cells/immunology , Lung/immunology , Lymphocytes/cytology , Pyroptosis , Sepsis/physiopathology , Animals , Caspase 1/genetics , Caspase 1/immunology , Endothelial Cells/cytology , Humans , Interleukin-33/genetics , Interleukin-33/immunology , Interleukin-9/genetics , Interleukin-9/immunology , Lung/cytology , Lymphocytes/immunology , Male , Mice , Mice, Inbred C57BL , Sepsis/genetics , Sepsis/immunology
10.
J Leukoc Biol ; 103(2): 175-183, 2018 02.
Article in English | MEDLINE | ID: mdl-28801344

ABSTRACT

Hemorrhagic shock (HS) renders patients susceptible to development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) through mechanisms that are, as yet, unclear. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. In this study, we investigated the mechanisms of alveolar macrophage (AMϕ) effects on PMN necroptosis following HS. With the use of in vivo and ex vivo HS models, we reveal a novel function of shock-activated AMϕ in promoting PMN necroptosis. We demonstrate that exosomes released from HS-activated AMϕ induce mainly NADPH oxidase-derived reactive oxygen species (ROS) production inside PMNs and subsequent promotion of necroptosis. These findings explore a previously unidentified pathway of AMϕ-PMN cross-talk, which causes enhanced PMN necroptosis and subsequent exaggerated post-HS lung inflammation. The targeting of this PMN death pathway may serve as a new therapeutic strategy for treatment of post-HS SIRS.


Subject(s)
Macrophages, Alveolar/pathology , Neutrophils/pathology , Shock, Hemorrhagic/pathology , Animals , Coculture Techniques , Disease Models, Animal , Exosomes/pathology , Humans , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , NADPH Oxidases/metabolism , Necrosis , Primary Cell Culture , Reactive Oxygen Species/metabolism
11.
J Immunol ; 199(9): 3176-3186, 2017 11 01.
Article in English | MEDLINE | ID: mdl-28947541

ABSTRACT

In elderly patients, bacterial infection often causes severe complications and sepsis. Compared to younger patients, older patients are more susceptible to sepsis caused by respiratory infection. Macrophage (Mϕ) phagocytosis of bacteria plays a critical role in the clearance of pathogens and the initiation of immune responses. It has been suggested that Mϕ exhibit age-related functional alterations, including reduced chemotaxis, phagocytosis, antibacterial defense, and the ability to generate reactive oxygen species. However, the mechanisms behind these changes remain unclear. The present study sought to determine changes in bacterial phagocytosis in aging alveolar Mϕ (AMϕ) and the underlying mechanisms. We show that bacteria initiate cytoskeleton remodeling in AMϕ through interaction with macrophage receptor with collagenous structure (MARCO), a bacterial scavenger receptor. This remodeling, in turn, promotes enhanced cell surface expression of MARCO and bacterial phagocytosis. We further demonstrate that Rac1-GTP mediates MARCO signaling and activates actin-related protein-2/3 complex, an F-actin nucleator, thereby inducing F-actin polymerization, filopodia formation, and increased cell surface expression of MARCO, all of which are essential for the execution of bacteria phagocytosis. However, AMϕ isolated from aging mice exhibit suppressed Rac1 mRNA and protein expression, which resulted in decreases in Rac1-GTP levels and actin-related protein-2/3 activation, as well as subsequent attenuation of F-actin polymerization, filopodia formation, and cell surface expression of MARCO. As a result, bacterial phagocytosis in aging AMϕ is decreased. This study highlights a previously unidentified mechanism by which aging impairs Mϕ phagocytosis of bacteria. Targeting these pathways may improve outcomes of bacterial infection in elderly patients.


Subject(s)
Actin Cytoskeleton/immunology , Aging/immunology , Escherichia coli K12/immunology , Macrophages, Alveolar/immunology , Phagocytosis/physiology , Actin Cytoskeleton/genetics , Aging/genetics , Animals , Humans , Male , Mice , Mice, Knockout , Neuropeptides/genetics , Neuropeptides/immunology , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , rac1 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/immunology
12.
Cell Death Dis ; 8(5): e2775, 2017 05 11.
Article in English | MEDLINE | ID: mdl-28492546

ABSTRACT

Trauma is a major cause of systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Macrophages (Mφ) direct trauma-induced inflammation, and Mφ death critically influences the progression of the inflammatory response. In the current study, we explored an important role of trauma in inducing mitochondrial DNA (mtDNA) damage in Mφ and the subsequent regulation of Mφ death. Using an animal pseudo-fracture trauma model, we demonstrated that tissue damage induced NADPH oxidase activation and increased the release of reactive oxygen species via cold-inducible RNA-binding protein (CIRP)-TLR4-MyD88 signaling. This in turn, activates endonuclease G, which serves as an executor for the fragmentation of mtDNA in Mφ. We further showed that fragmented mtDNA triggered both p62-related autophagy and necroptosis in Mφ. However, autophagy activation also suppressed Mφ necroptosis and pro-inflammatory responses. This study demonstrates a previously unidentified intracellular regulation of Mφ homeostasis in response to trauma.


Subject(s)
Autophagy , DNA Fragmentation , DNA, Mitochondrial/metabolism , Macrophages/metabolism , RNA-Binding Proteins/metabolism , Signal Transduction , Toll-Like Receptor 4/metabolism , Wounds and Injuries/metabolism , Animals , DNA, Mitochondrial/genetics , Macrophages/pathology , Mice , Mice, Knockout , RNA-Binding Proteins/genetics , Toll-Like Receptor 4/genetics , Wounds and Injuries/genetics , Wounds and Injuries/pathology
13.
Immunology ; 151(4): 417-432, 2017 08.
Article in English | MEDLINE | ID: mdl-28375544

ABSTRACT

Formation of neutrophil extracellular traps (NETs) is an important function of the innate immune system against infections. It has been proven that aging dysregulates immunity and impairs neutrophil function. However, the influence of aging on the ability to produce NETs has yet to be fully addressed. In this study, we tested the hypothesis that a lower level of autophagy in neutrophils from aged mice was responsible for the decrease in NET formation. We demonstrated that a broad range of Toll-like receptor 2 (TLR2) ligands could efficiently induce reactive oxygen species (ROS) -dependent NET release in young mice, but not in aged ones. We further explored that the difference between young and aged mice in TLR2 ligand-induced NETosis is the result of an Atg5 defect and subsequent impaired autophagy. Furthermore, we found that lower autophagy capacity led to not only reduced NET formation, but also increased apoptosis. Our results suggest an important role of Atg5 and autophagy in maintaining the function of NETs formation in response to infection and in regulating neutrophil death. Targeting autophagy-promoted NETs may present a therapeutic strategy to improve infection defence in an aged population.


Subject(s)
Aging/immunology , Autophagy-Related Protein 5/metabolism , Autophagy , Extracellular Traps/immunology , Neutrophils/immunology , Animals , Autophagy-Related Protein 5/genetics , Cells, Cultured , Immunity, Innate , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophil Activation , Reactive Oxygen Species/metabolism , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/metabolism
14.
Sci Rep ; 6: 31663, 2016 08 16.
Article in English | MEDLINE | ID: mdl-27526865

ABSTRACT

Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary infection. Alveolar macrophages (AM) are at the center of the pathogenesis of the development of ALI. Interleukin-1ß (IL-1ß) is one of the key pro-inflammatory mediators, and its maturation is tightly controlled by the formation and activation of the inflammasome. The biological effects of IL-1ß are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1ß release and IL-1RI upregulation on the development of lung inflammation. We demonstrated that in AM, LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1ß, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-κB dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1ß and results in pyroptosome formation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death. We further showed that AM pyroptosis exaggerates lung inflammation. The present study demonstrates a novel mechanism underlying LPS-induced innate immunity; that is, a secondary upregulation of IL-1ß-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS.


Subject(s)
Acute Lung Injury/immunology , Interleukin-1beta/physiology , Macrophages, Alveolar/immunology , Pneumonia/immunology , Pyroptosis/immunology , Receptors, Interleukin-1/physiology , Toll-Like Receptor 4/physiology , Animals , Bronchoalveolar Lavage Fluid , Cytokines/metabolism , Inflammasomes/metabolism , Lipopolysaccharides/administration & dosage , Macrophages, Alveolar/pathology , Male , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Up-Regulation
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