49 results on '"Mashayekhi, Mona"'
Search Results
2. Immune Cell Activation in Obesity and Cardiovascular Disease
- Author
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Garcia, Jamie N., Wanjalla, Celestine N., Mashayekhi, Mona, and Hasty, Alyssa H.
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- 2022
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3. Hematologic malignancies magnify the effect of body mass index on insulin resistance in cancer survivors
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Sahinoz, Melis, Luther, James M., Mashayekhi, Mona, Jung, Dae Kwang, Ikizler, T. Alp, and Engelhardt, Brian G.
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- 2022
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4. The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose.
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Mashayekhi, Mona, Sheng, Quanhu, Bailin, Samuel S., Massier, Lucas, Zhong, Jiawei, Shi, Mingjian, Wanjalla, Celestine N., Wang, Thomas J., Ikizler, T. Alp, Niswender, Kevin D., Gabriel, Curtis L., Palacios, Julia, Turgeon‐Jones, Rachel, Reynolds, Cassandra F., Luther, James M., Brown, Nancy J., Das, Saumya, Dahlman, Ingrid, Mosley, Jonathan D., and Koethe, John R.
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INSULIN resistance ,LOCUS (Genetics) ,GENE expression ,TYPE 2 diabetes ,BARIATRIC surgery ,GASTRIC bypass - Abstract
Objective: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity. Methods: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping. Results: We identified a 35‐gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non‐immune cell populations. We observed primarily "protective" IR associations for adipocyte transcripts and "deleterious" associations for macrophage transcripts, as well as a high concordance between SAT and visceral adipose tissue (VAT). Multiple SAT genes exhibited dynamic expression 5 years after weight loss surgery and with insulin stimulation. Using available expression quantitative trait loci in SAT and/or VAT, we demonstrated similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI. Conclusions: SAT is conventionally viewed as a metabolic buffer for lipid deposition during positive energy balance, whereas VAT is viewed as a dominant contributor to and prime mediator of IR and cardiometabolic disease risk. Our results implicate a dynamic transcriptional architecture of IR that resides in both immune and non‐immune populations in SAT and is shared with VAT, nuancing the current VAT‐centric concept of IR in humans. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Single-cell analysis shows that adipose tissue of persons with both HIV and diabetes is enriched for clonal, cytotoxic, and CMV-specific CD4+ T cells
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Wanjalla, Celestine N., McDonnell, Wyatt J., Ram, Ramesh, Chopra, Abha, Gangula, Rama, Leary, Shay, Mashayekhi, Mona, Simmons, Joshua D., Warren, Christian M., Bailin, Samuel, Gabriel, Curtis L., Guo, Liang, Furch, Briana D., Lima, Morgan C., Woodward, Beverly O., Hannah, LaToya, Pilkinton, Mark A., Fuller, Daniela T., Kawai, Kenji, Virmani, Renu, Finn, Aloke V., Hasty, Alyssa H., Mallal, Simon A., Kalams, Spyros A., and Koethe, John R.
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- 2021
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6. Interleukin-17A is associated with flow-mediated dilation and interleukin-4 with carotid plaque in persons with HIV
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Wanjalla, Celestine N., Temu, Tecla M., Mashayekhi, Mona, Warren, Christian M., Shepherd, Bryan E., Gangula, Rama, Fuseini, Hubaida, Bailin, Samuel, Gabriel, Curtis L., Gangula, Pandu, Madhur, Meena S., Kalams, Spyros, Mallal, Simon A., Harrison, David G., Beckman, Joshua A., and Koethe, John R.
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- 2022
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7. DPP4 (Dipeptidyl Peptidase-4) Inhibition Increases Catecholamines Without Increasing Blood Pressure During Sustained ACE (Angiotensin-Converting Enzyme) Inhibitor Treatment
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Wilson, Jessica R., Garner, Erica M., Mashayekhi, Mona, Hubers, Scott A., Ramirez Bustamante, Claudia E., Kerman, Scott Jafarian, Nian, Hui, Shibao, Cyndya A., and Brown, Nancy J.
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- 2022
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8. Weight Loss–Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes.
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Mashayekhi, Mona, Nian, Hui, Mayfield, Dustin, Devin, Jessica K., Gamboa, Jorge L., Yu, Chang, Silver, Heidi J., Niswender, Kevin, Luther, James M., and Brown, Nancy J.
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GASTRIC inhibitory polypeptide , *INSULIN sensitivity , *LIRAGLUTIDE , *GLUCAGON-like peptide 1 , *CD26 antigen , *PREDIABETIC state - Abstract
Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss–independent, GLP-1R–dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss–independent, GLP-1R–dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. Article Highlights: Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss–independent, GLP-1 receptor (GLP-1R)–dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R–dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss–independent, GLP-1R–dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Metaflammation in obesity and its therapeutic targeting.
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Schleh, Michael W., Caslin, Heather L., Garcia, Jamie N., Mashayekhi, Mona, Srivastava, Gitanjali, Bradley, Anna B., and Hasty, Alyssa H.
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ADIPOSE tissues ,OBESITY ,METABOLIC regulation ,IMMUNOLOGIC memory ,COMPULSIVE eating ,IMMUNE system ,PSYCHONEUROIMMUNOLOGY - Abstract
Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune populations. Here, we review the current literature on the roles of various immune cells in lean and obese adipose tissue. Within this context, we discuss pharmacological and nonpharmacological approaches to obesity treatment and their impact on systemic inflammation. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Changes in subcutaneous white adipose tissue cellular composition and molecular programs underlie glucose intolerance in persons with HIV.
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Bailin, Samuel S., Kropski, Jonathan A., Gangula, Rama D., Hannah, LaToya, Simmons, Joshua D., Mashayekhi, Mona, Fei Ye, Run Fan, Mallal, Simon, Warren, Christian M., Kalams, Spyros A., Gabriel, Curtis L., Wanjalla, Celestine N., and Koethe, John R.
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WHITE adipose tissue ,GLUCOSE intolerance ,CELL communication ,METABOLIC disorders ,METABOLIC regulation ,TYPE 2 diabetes - Abstract
Introduction: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. Methods: We generated a comprehensive single-cell multi-omic SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH across a spectrum of metabolic health. Results: Glucose intolerance was associated with increased lipid-associated macrophages, CD4
+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4+ effector memory tissue-resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Intercellular communication analysis demonstrated enhanced proinflammatory and pro-fibrotic signaling between immune cells and stromal cells in PWH with glucose intolerance compared with non-diabetic PWH. Lastly, while cell type-specific gene expression among PWH with diabetes was globally similar to HIV-negative individuals with diabetes, we observed substantially divergent intercellular communication pathways. Discussion: These findings suggest a central role of tissue-resident immune cells in regulating SAT inflammation among PWH with metabolic disease, and underscore unique mechanisms that may converge to promote metabolic disease. [ABSTRACT FROM AUTHOR]- Published
- 2023
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11. Effect of the glucagon‐like peptide‐1 receptor agonist liraglutide, compared to caloric restriction, on appetite, dietary intake, body fat distribution and cardiometabolic biomarkers: A randomized trial in adults with obesity and prediabetes.
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Silver, Heidi J., Olson, Dianna, Mayfield, Dustin, Wright, Patricia, Nian, Hui, Mashayekhi, Mona, Koethe, John R., Niswender, Kevin D., Luther, James M., and Brown, Nancy J.
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FAT ,WEIGHT loss ,GLUCAGON-like peptide-1 receptor ,GLUCAGON-like peptide-1 agonists ,LOW-calorie diet ,DUAL-energy X-ray absorptiometry ,FOOD consumption - Abstract
Aims: To investigate the hypothesis that weight loss with the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) liraglutide alone would lead to a greater reduction in the proportion of fat to lean tissue mass when compared to caloric restriction (CR) alone, as well as when compared to treatment with sitagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, that also enhances GLP‐1 activity ‐ to determine the independent effects of each treatment. Methods: A total of 88 adults with obesity and prediabetes were randomized to 14 weeks of intervention with CR (−390 kcal/d), liraglutide (1.8 mg/d), or the dipeptidyl peptidase‐4 inhibitor sitagliptin (100 mg/d) as a weight‐neutral comparator. Changes between groups in appetite and hunger ratings measured via visual analogue scales, dietary intakes, body weight, body composition via dual energy x‐ray absorptiometry, and resting energy expenditure via indirect calorimetry were assessed using the Kruskal‐Wallis test or Pearson's chi‐squared test. Results: Weight loss ≥5% of baseline body weight occurred in 44% of participants in the CR group, 22% of the liraglutide group and 5% of the sitagliptin group (p = 0.02). The ratio of fat to lean mass decreased by 6.5% in the CR group, 2.2% in the liraglutide group, and 0% in the sitagliptin group (p = 0.02). Visceral fat reduced by 9.5% in the CR group, 4.8% in the liraglutide group, and 0% in the sitagliptin group (p = 0.04). A spontaneous reduction in dietary simple carbohydrates in the CR group was associated with improved homeostatic model assessment of insulin resistance score (HOMA‐IR). Conclusions: Although both liraglutide and CR are valuable strategies for cardiometabolic risk reduction, CR was associated with greater weight loss and more favourable improvements in body composition than treatment with liraglutide alone. Differences in the response to each of these interventions enables patients to be stratified to the most optimal intervention for their personal risk factors. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells
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Miller, Michelle L., Mashayekhi, Mona, Chen, Luqiu, Zhou, Ping, Liu, Xindong, Michelotti, Monica, Gunn, Nicole Tramontini, Powers, Sarah, Zhu, Xiaoping, Evaristo, Cesar, Alegre, Maria-Luisa, and Molinero, Luciana L.
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- 2014
13. Glucagon‐like peptide‐1 receptor agonist use is associated with lower serum periostin.
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Foer, Dinah, Beeler, Patrick E., Cui, Jing, Snyder, William E., Mashayekhi, Mona, Nian, Hui, Luther, James M., Karlson, Elizabeth W., Boyce, Joshua A., and Cahill, Katherine N.
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GLUCAGON-like peptide-1 receptor ,GLUCAGON-like peptide-1 agonists ,PERIOSTIN - Abstract
Serum periostin is lower in asthmatics with T2DM using GLP-1RAs compared to alternative diabetes therapies. Prior studies identifying candidate biomarkers of GLP-1RA use critically lacked inclusion of patients with asthma.[[4]] Increasing data support periostin as a potential biomarker of GLP-1RA use. In conclusion, GLP-1RA use may attenuate the increased risk for poor asthma outcomes in patients with metabolic dysregulation and obesity by impacting pathways relevant to airway inflammation in humans. Consistent with prior asthma literature, patients with comorbid asthma (Biobank cohort) had higher mean levels of periostin than the non-asthma patients (RCT cohort). [Extracted from the article]
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- 2023
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14. Glucagon-Like Peptide-1 Receptor Regulates Thromboxane-Induced Human Platelet Activation
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Cahill, Katherine N., Amin, Taneem, Boutaud, Olivier, Printz, Richard, Newcomb, Dawn C., Foer, Dinah, Hodson, David J., Broichhagen, Johannes, Beckman, Joshua A., Yu, Chang, Nian, Hui, Mashayekhi, Mona, Silver, Heidi J., Luther, James M., Brown, Nancy J., Peebles, R. Stokes, Jr, and Niswender, Kevin
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- 2022
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15. CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV.
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Wanjalla, Celestine N., Gabriel, Curtis L., Fuseini, Hubaida, Bailin, Samuel S., Mashayekhi, Mona, Simmons, Joshua, Warren, Christopher M., Glass, David R., Oakes, Jared, Gangula, Rama, Wilfong, Erin, Priest, Stephen, Temu, Tecla, Newell, Evan W., Pakala, Suman, Kalams, Spyros A., Gianella, Sara, Smith, David, Harrison, David G., and Mallal, Simon A.
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FATTY liver ,T cells ,HEART metabolism disorders ,CARNITINE palmitoyltransferase ,NON-alcoholic fatty liver disease ,CHEMOKINE receptors - Abstract
Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1
+ , GPR56+ , and CD57+ /- T cells (termed CGC+ ) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on longterm ART. We found that PWH with cardiometabolic diseases (non-alcoholic fatty liver disease, calcified coronary arteries, or diabetes) had higher circulating CGC+ CD4+ T cells compared to metabolically healthy PWH. The traditional risk factor most correlated with CGC+CD4+ T cell frequency was fasting blood glucose, as well as starch/sucrose metabolites. While unstimulated CGC+ CD4+ T cells, like other memory T cells, depend on oxidative phosphorylation for energy, they exhibited higher expression of carnitine palmitoyl transferase 1A compared to other CD4+ T cell subsets, suggesting a potentially greater capacity for fatty acid boxidation. Lastly, we show that CMV-specific T cells against multiple viral epitopes are predominantly CGC+ . Together, this study suggests that among PWH, CGC+ CD4+ T cells are frequently CMV-specific and are associated with diabetes, coronary arterial calcium, and non-alcoholic fatty liver disease. Future studies should assess whether anti-CMV therapies could reduce cardiometabolic disease risk in some individuals. [ABSTRACT FROM AUTHOR]- Published
- 2023
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16. Comparative effects of weight loss and incretin‐based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial.
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Mashayekhi, Mona, Beckman, Joshua A., Nian, Hui, Garner, Erica M., Mayfield, Dustin, Devin, Jessica K., Koethe, John R., Brown, Jonathan D., Cahill, Katherine N., Yu, Chang, Silver, Heidi, Niswender, Kevin, Luther, James M., and Brown, Nancy J.
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WEIGHT loss , *RANDOMIZED controlled trials , *PREDIABETIC state , *FIBRINOLYSIS , *CD26 antigen , *GLUCAGON-like peptide-1 receptor , *PLASMINOGEN - Abstract
Aim: To test the hypothesis that glucagon‐like peptide‐1 receptor (GLP‐1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss‐independent mechanisms. Materials and Methods: Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP‐1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase‐4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo‐controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow‐mediated vasodilation (FMD), plasminogen activator inhibitor‐1 (PAI‐1) and urine albumin‐to‐creatinine ratio (UACR). Results: Eighty‐eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI‐1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP‐1R antagonism with exendin (9‐39) increased fasting blood glucose but did not change FMD or PAI‐1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein‐1 (MCP‐1). Conclusion: Liraglutide and diet reduce weight, insulin resistance and PAI‐1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro‐inflammatory and pro‐atherosclerotic chemokine MCP‐1, indicating that this beneficial effect is independent of weight loss. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Mean Coronary Cross-Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV.
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Werede, Ayoda T., Terry, James G., Nair, Sangeeta, Temu, Tecla M., Shepherd, Bryan E., Bailin, Samuel S., Mashayekhi, Mona, Gabriel, Curtis L., Lima, Morgan, Woodward, Beverly Owen, Hannah, LaToya, Mallal, Simon A., Beckman, Joshua A., Li, Jonathan Z., Fajnzylber, Jesse, Harrison, David G., Carr, John Jeffrey, Koethe, John R., Wanjalla, Celestine N., and Harrison, David
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- 2022
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18. Compensatory dendritic cell development mediated by BATF–IRF interactions
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Tussiwand, Roxane, Lee, Wan-Ling, Murphy, Theresa L., Mashayekhi, Mona, KC, Wumesh, Albring, Jörn C., Satpathy, Ansuman T., Rotondo, Jeffrey A., Edelson, Brian T., Kretzer, Nicole M., Wu, Xiaodi, Weiss, Leslie A., Glasmacher, Elke, Li, Peng, Liao, Wei, Behnke, Michael, Lam, Samuel S. K., Aurthur, Cora T., Leonard, Warren J., Singh, Harinder, Stallings, Christina L., Sibley, L. David, Schreiber, Robert D., and Murphy, Kenneth M.
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- 2012
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19. Relationship of Subcutaneous Adipose Tissue Inflammation–Related Gene Expression With Ectopic Lipid Deposition in Persons With HIV.
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Bailin, Samuel S., Gabriel, Curtis L., Fan, Run, Ye, Fei, Nair, Sangeeta, Terry, James G., Carr, John J., Silver, Heidi, Wanjalla, Celestine N., Mashayekhi, Mona, Lima, Morgan, Woodward, Beverly, Hannah, LaToya, Fuseini, Hubaida, Ferguson, Jane F., Kropski, Jonathan A., and Koethe, John R.
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- 2022
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20. Sa1608 BACTERIA-RELATED METABOLITES AND METABOLIC PATHWAYS ARE ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE IN PERSONS WITH HIV
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Gabriel, Curtis L., Wanjalla, Celestine N., Mashayekhi, Mona, Bailin, Sam, Koethe, John, and Ferguson, Jane
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- 2023
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21. CD8α+ Dendritic Cells Are the Critical Source of Interleukin-12 that Controls Acute Infection by Toxoplasma gondii Tachyzoites
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Mashayekhi, Mona, Sandau, Michelle M., Dunay, Ildiko R., Frickel, Eva M., Khan, Asis, Goldszmid, Romina S., Sher, Alan, Ploegh, Hidde L., Murphy, Theresa L., Sibley, David L., and Murphy, Kenneth M.
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- 2011
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22. GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans.
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Luther, James M., Ray, Justina, Dawei Wei, Koethe, John R., Hannah, Latoya, DeMatteo, Anthony, Manning, Robert, Terker, Andrew S., Dungeng Peng, Hui Nian, Chang Yu, Mashayekhi, Mona, Gamboa, Jorge, Brown, Nancy J., Wei, Dawei, Peng, Dungeng, Nian, Hui, and Yu, Chang
- Abstract
[Figure: see text]. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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23. Hepatic Steatosis and Ectopic Fat Are Associated With Differences in Subcutaneous Adipose Tissue Gene Expression in People With HIV.
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Gabriel, Curtis L., Ye, Fei, Fan, Run, Nair, Sangeeta, Terry, James G., Carr, John Jeffrey, Silver, Heidi, Baker, Paxton, Hannah, LaToya, Wanjalla, Celestine, Mashayekhi, Mona, Bailin, Sam, Lima, Morgan, Woodward, Beverly, Izzy, Manhal, Ferguson, Jane F., and Koethe, John R.
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HIV-positive persons ,ADIPOSE tissue diseases ,GENE expression in mammals - Abstract
Persons with human immunodeficiency virus (PWH) have subcutaneous adipose tissue (SAT) dysfunction related to antiretroviral therapy and direct viral effects, which may contribute to a higher risk of nonalcoholic fatty liver disease compared with human immunodeficiency virus–negative individuals. We assessed relationships between SAT expression of major adipocyte regulatory and lipid storage genes with hepatic and other ectopic lipid deposits in PWH. We enrolled 97 PWH on long‐term antiretroviral therapy with suppressed plasma viremia and performed computed tomography measurements of liver attenuation, a measure of hepatic steatosis, skeletal muscle (SM) attenuation, and the volume of abdominal subcutaneous, visceral, and pericardial adipose tissue. Whole SAT gene expression was measured using the Nanostring platform, and relationships with computed tomography imaging and fasting lipids were assessed using multivariable linear regression and network mapping. The cohort had a mean age of 47 years, body mass index of 33.4 kg/m2, and CD4 count of 492 cells/mm3. Lower liver attenuation, a marker of greater steatosis, was associated with differences in SAT gene expression, including lower lipoprotein lipase and acyl‐CoA dehydrogenase, and higher phospholipid transfer protein. Lower liver attenuation clustered with lower visceral adipose tissue (VAT) attenuation and greater VAT volume, pericardial fat volume and triglycerides, but no relationship was observed between liver attenuation and SAT volume, SM attenuation, or low‐density lipoprotein. Conclusion: Liver attenuation was associated with altered SAT expression of genes regulating lipid metabolism and storage, suggesting that SAT dysfunction may contribute to nonalcoholic fatty liver disease in PWH. SAT gene‐expression relationships were similar for VAT volume and attenuation, but not SM, indicating that ectopic lipid deposition may involve multiple pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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24. Anticytomegalovirus CD4+ T Cells Are Associated With Subclinical Atherosclerosis in Persons With HIV.
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Wanjalla, Celestine N., Mashayekhi, Mona, Bailin, Samuel, Gabriel, Curtis L., Meenderink, Leslie M., Temu, Tecla, Fuller, Daniella T., Guo, Liang, Kawai, Kenji, Virmani, Renu, Jenkins, Cathy, Abana, Chike O., Warren, Christian M., Gangula, Rama, Smith, Rita, Madhur, Meena S., Finn, Aloke V., Gelbard, Alexander H., Su, Yan Ru, and Tyska, Matthew J.
- Published
- 2021
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25. Association of a glucagon‐like peptide‐1 receptor gene variant with glucose response to a mixed meal.
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Mashayekhi, Mona, Wilson, Jessica R., Jafarian‐Kerman, Scott, Nian, Hui, Yu, Chang, Shuey, Megan M., Luther, James M., and Brown, Nancy J.
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GLUCAGON-like peptide-1 receptor , *SODIUM-glucose cotransporters , *TYPE 2 diabetes , *GLUCOSE , *NUCLEIC acids , *GLUCAGON-like peptide 1 - Abstract
Dipeptidyl peptidase‐4 (DPP‐4) inhibitors increase endogenous glucagon‐like peptide‐1 (GLP‐1). We hypothesized that genetic variation in the gene encoding the GLP‐1 receptor (GLP1R) could affect the metabolic response to DPP‐4 inhibition. To evaluate the relationship between the GLP1R rs6923761 variant (G‐to‐A nucleic acid substitution) and metabolic responses, we performed mixed meal studies in individuals with type 2 diabetes mellitus and hypertension after 7‐day treatment with placebo and the DPP‐4 inhibitor sitagliptin. This analysis is a substudy of NCT02130687. The genotype frequency was 13:12:7 GG:GA:AA among individuals of European ancestry. Postprandial glucose excursion was significantly decreased in individuals carrying the rs6923761 variant (GA or AA) as compared with GG individuals during both placebo (P = 0.001) and sitagliptin treatment (P = 0.045), while intact GLP‐1 levels were similar among the genotype groups. In contrast, sitagliptin lowered postprandial glucose to a greater degree in GG as compared with GA/AA individuals (P = 0.035). The relationship between GLP1R rs6923761 genotype and therapies that modulate GLP‐1 signalling merits study in large populations. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. Sa348 THE PLASMA LIPIDOME DIFFERENTIATES NAFLD IN HIV-POSITIVE PERSONS FROM NAFLD IN HIV-NEGATIVE PERSONS
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Gabriel, Curtis L., Wanjalla, Celestine, Bailin, Sam, Mashayekhi, Mona, Ferguson, Jane, and Koethe, John
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- 2021
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27. SUBCUTANEOUS ADIPOSE TISSUE CELL COMPOSITION IS ASSOCIATED WITH VISCERAL FAT VOLUME.
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Bailin, Samuel S., Carr, John J., Nair, Sangeeta, Silver, Heidi J., Mashayekhi, Mona, Gabriel, Curtis L., Gangula, Rama, Hannah, Latoya, Kropski, Jonathan A., Kalams, Spyros A., Mallal, Simon A., Koethe, John R., and Wanjalla, Celestine N.
- Published
- 2023
28. Abstract #357 Pseudohypoglycemia in Severe Peripheral Artery Diseasecase Report and Literature Review
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Matthews, Juliana, Mashayekhi, Mona, and Hendrickson, Chase
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- 2019
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29. 418 Activation of the Glucagon-Like Peptide-1 Pathway in Obese Pre-Diabetic Individuals Improves Endothelial Function Independently of Weight Loss.
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Mashayekhi, Mona, Beckman, Joshua A., Garner, Erica M., Nian, Hui, Yu, Chang, Howard, Sara E., Perkins, Bradley, Devin, Jessica K., Koethe, John R., Brown, Jonathan D., Silver, Heidi, Luther, James M., and Brown, Nancy J.
- Subjects
WEIGHT loss ,OBESITY ,REDUCING diets ,BETA lactam antibiotics ,THERAPEUTICS ,NEURAL stem cells ,CEREBRAL circulation - Published
- 2022
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30. The soluble epoxide hydrolase inhibitor GSK2256294 decreases the proportion of adipose pro-inflammatory T cells.
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Mashayekhi, Mona, Wanjalla, Celestine N., Warren, Christian M., Simmons, Joshua D., Ghoshal, Kakali, Pilkinton, Mark, Bailin, Samuel S., Gabriel, Curtis L., Pozzi, Ambra, Koethe, John R., Brown, Nancy J., Kalams, Spyros A., and Luther, J. Matthew
- Subjects
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EPOXIDE hydrolase , *T cells , *ABDOMINAL adipose tissue , *ADIPOSE tissue physiology , *T helper cells , *TUMOR necrosis factors - Abstract
• sEH inhibition decreases adipose tissue IFNγ-producing T helper cells and secreted TNFα. • sEH inhibition does not affect adipose tissue IL-17A production. • Modulating the sEH/EET pathway has anti-inflammatory potential in humans. Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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31. The Polymorphic Pseudokinase ROP5 Controls Virulence in Toxoplasma gondii by Regulating the Active Kinase ROP18.
- Author
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Behnke, Michael S., Fentress, Sarah J., Mashayekhi, Mona, Li, Lucy X., Taylor, Gregory A., and Sibley, L. David
- Subjects
MICROBIAL virulence ,PATHOGENIC microorganisms ,TOXOPLASMA gondii ,TOXOPLASMA ,KINASES - Abstract
Secretory polymorphic serine/threonine kinases control pathogenesis of Toxoplasma gondii in the mouse. Genetic studies show that the pseudokinase ROP5 is essential for acute virulence, but do not reveal its mechanism of action. Here we demonstrate that ROP5 controls virulence by blocking IFN-γ mediated clearance in activated macrophages. ROP5 was required for the catalytic activity of the active S/T kinase ROP18, which phosphorylates host immunity related GTPases (IRGs) and protects the parasite from clearance. ROP5 directly regulated activity of ROP18 in vitro, and both proteins were necessary to avoid IRG recruitment and clearance in macrophages. Clearance of both the Δrop5 and Δrop18 mutants was reversed in macrophages lacking Irgm3, which is required for IRG function, and the virulence defect was fully restored in Irgm3
-/- mice. Our findings establish that the pseudokinase ROP5 controls the activity of ROP18, thereby blocking IRG mediated clearance in macrophages. Additionally, ROP5 has other functions that are also Irgm3 and IFN-γ dependent, indicting it plays a general role in governing virulence factors that block immunity. [ABSTRACT FROM AUTHOR]- Published
- 2012
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32. CD8α+ Dendritic Cells Are the Critical Source of Interleukin-12 that Controls Acute Infection by Toxoplasma gondii Tachyzoites
- Author
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Mashayekhi, Mona, Sandau, Michelle M., Dunay, Ildiko R., Frickel, Eva M., Khan, Asis, Goldszmid, Romina S., Sher, Alan, Ploegh, Hidde L., Murphy, Theresa L., Sibley, L. David, and Murphy, Kenneth M.
- Subjects
- *
DENDRITIC cells , *INTERLEUKIN-12 , *TOXOPLASMA gondii , *PROTOZOAN diseases , *NATURAL immunity , *CELLULAR immunity , *PREVENTION - Abstract
Summary: CD8α+ dendritic cells (DCs) are important in vivo for cross-presentation of antigens derived from intracellular pathogens and tumors. Additionally, secretion of interleukin-12 (IL-12) by CD8α+ DCs suggests a role for these cells in response to Toxoplasma gondii antigens, although it remains unclear whether these cells are required for protection against T. gondii infection. Toward this goal, we examined T. gondii infection of Batf3 −/− mice, which selectively lack only lymphoid-resident CD8α+ DCs and related peripheral CD103+ DCs. Batf3 −/− mice were extremely susceptible to T. gondii infection, with decreased production of IL-12 and interferon-γ. IL-12 administration restored resistance in Batf3−/− mice, and mice in which IL-12 production was ablated only from CD8α+ DCs failed to control infection. These results reveal that the function of CD8α+ DCs extends beyond a role in cross-presentation and includes a critical role for activation of innate immunity through IL-12 production during T. gondii infection. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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33. Phosphorylation of Immunity-Related GTPases by a Toxoplasma gondii-Secreted Kinase Promotes Macrophage Survival and Virulence.
- Author
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Fentress, Sarah J., Behnke, Michael S., Dunay, Ildiko R., Mashayekhi, Mona, Rommereim, Leah M., Fox, Barbara A., Bzik, David J., Taylor, Gregory A., Turk, Benjamin E., Lichti, Cheryl F., Townsend, R. Reid, Qiu, Wei, Hui, Raymond, Beatty, Wandy L., and Sibley, L. David
- Subjects
PHOSPHORYLATION ,GUANOSINE triphosphatase ,TOXOPLASMA gondii ,MACROPHAGES ,PROTEIN kinases ,MICROBIAL virulence ,INTRACELLULAR pathogens ,GENE expression - Abstract
Summary: Macrophages are specialized to detect and destroy intracellular microbes and yet a number of pathogens have evolved to exploit this hostile niche. Here we demonstrate that the obligate intracellular parasite Toxoplasma gondii disarms macrophage innate clearance mechanisms by secreting a serine threonine kinase called ROP18, which binds to and phosphorylates immunity-related GTPases (IRGs). Substrate profiling of ROP18 revealed a preference for a conserved motif within switch region I of the GTPase domain, a modification predicted to disrupt IRG function. Consistent with this, expression of ROP18 was both necessary and sufficient to block recruitment of Irgb6, which was in turn required for parasite destruction. ROP18 phosphorylation of IRGs prevented clearance within inflammatory monocytes and IFN-γ-activated macrophages, conferring parasite survival in vivo and promoting virulence. IRGs are implicated in clearance of a variety of intracellular pathogens, suggesting that other virulence factors may similarly thwart this innate cellular defense mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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34. Livedoid Dermatitis Treated With Nifedipine.
- Author
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Wheless, Lee, Lilly Zhu, Mashayekhi, Mona, and Fissell, Rachel B.
- Published
- 2016
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35. Mesp1 Coordinately Regulates Cardiovascular Fate Restriction and Epithelial-Mesenchymal Transition in Differentiating ESCs.
- Author
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Lindsley, R. Coleman, Gill, Jennifer G., Murphy, Theresa L., Langer, Ellen M., Mi Cai, Mashayekhi, Mona, Wei Wang, Niwa, Noriko, Nerbonne, Jeanne M., Kyba, Michael, and Murphy, Kenneth M.
- Subjects
PROTEINS ,STEM cells ,EMBRYONIC stem cells ,MESODERM ,GASTRULATION - Abstract
Wnt signaling is required for development of mesoderm-derived lineages and expression of transcription factors associated with the primitive streak. In a functional screen, we examined the mesoderm-inducing capacity of transcription factors whose expression was Wnt-dependent in differentiating ESCs. In contrast to many inactive factors, we found that mesoderm posterior 1 (Mesp1) promoted mesoderm development independently of Wnt signaling. Transient Mesp 1 expression in ESCs promotes changes associated with epithelial-mesenchymal transition (EMT) and induction of Snai1, consistent with a role in gastrulation. Mesp1 expression also restricted the potential fates derived from ESCs, generating mesoderm progenitors with cardiovascular, but not hematopoietic, potential. Thus, in addition to its effects on EMT, Mesp1 may be capable of generating the recently identified multipotent cardiovascular progenitor from ESCs in vitro. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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36. Hedgehog signaling controls thymocyte progenitor homeostasis and differentiation in the thymus.
- Author
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El Andaloussi, Abdeljabar, Graves, Stephanie, Fanyong Meng, Mandal, Malay, Mashayekhi, Mona, and Aifantis, Iannis
- Subjects
THYMUS ,HEDGEHOG signaling proteins ,HOMEOSTASIS ,CELL differentiation ,T cell receptors ,TRANSCRIPTION factors - Abstract
Commitment of hematopoietic progenitors to the T cell lineage requires the integration of multiple signaling pathways. Evidence has suggested involvement of hedgehog (Hh) signaling in T cell differentiation through its signal transducer smoothened (Smo). However, the precise function of the Hh pathway remains controversial, mainly because T cell–specific in vivo genetic models have not been used. Using pre–T cell–specific, mature T cell–specific and poly(I)·poly(C)-inducible deletions of Smo and antagonists of Smo signaling, we report here that Hh is an essential positive regulator of T cell progenitor differentiation. Furthermore, we localize Hh function to a stage preceding pre–T cell receptor signaling, connect Smo signaling to the activity of the Gli1 and Gli2 transcription factors and demonstrate that Hh affects regulators of thymocyte survival and proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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37. CD3 + T-cell: CD14 + monocyte complexes are dynamic and increased with HIV and glucose intolerance.
- Author
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Obare LM, Simmons J, Oakes J, Zhang X, Nochowicz C, Priest S, Bailin SS, Warren CM, Mashayekhi M, Beasley HK, Shao J, Meenderink LM, Sheng Q, Stolze J, Gangula R, Absi T, Su YR, Neikirk K, Chopra A, Gabriel CL, Temu T, Pakala S, Wilfong EM, Gianella S, Phillips EJ, Harrison DG, Hinton A, Kalams SA, Kirabo A, Mallal SA, Koethe JR, and Wanjalla CN
- Abstract
An increased risk of cardiometabolic disease accompanies persistent systemic inflammation. Yet, the innate and adaptive immune system features in persons who develop these conditions remain poorly defined. Doublets, or cell-cell complexes, are routinely eliminated from flow cytometric and other immune phenotyping analyses, which limits our understanding of their relationship to disease states. Using well-characterized clinical cohorts, including participants with controlled HIV as a model for chronic inflammation and increased immune cell interactions, we show that circulating CD14
+ monocytes complexed to CD3+ T cells are dynamic, biologically relevant, and increased in individuals with diabetes after adjusting for confounding factors. The complexes form functional immune synapses with increased expression of proinflammatory cytokines and greater glucose utilization. Furthermore, in persons with HIV, the CD3+ T-cell: CD14+ monocyte complexes had more HIV copies compared to matched CD14+ monocytes or CD4+ T cells alone. Our results demonstrate that circulating CD3+ T-cell:CD14+ monocyte pairs represent dynamic cellular interactions that may contribute to inflammation and cardiometabolic disease pathogenesis and may originate or be maintained, in part, by chronic viral infections. These findings provide a foundation for future studies investigating mechanisms linking T cellmonocyte cell-cell complexes to developing immune-mediated diseases, including HIV and diabetes., Competing Interests: Declaration of interests The authors have no competing interests.- Published
- 2024
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38. Single-cell Analysis of Subcutaneous Fat Reveals Pro-fibrotic Cells that Correlate with Visceral Adiposity in HIV.
- Author
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Bailin SS, Gabriel CL, Gangula RD, Hannah L, Nair S, Carr JJ, Terry JG, Silver HJ, Simmons JD, Mashayekhi M, Kalams SA, Mallal S, Kropski JA, Wanjalla CN, and Koethe JR
- Abstract
Context: Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH., Objective: We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART., Methods: We enrolled PWH on long-term ART with a spectrum of metabolic health. Ninety-two participants underwent SAT biopsy for bulk RNA sequencing and 43 had single-cell RNA sequencing. Computed tomography quantified VAT volume and insulin resistance was calculated using HOMA2-IR., Results: VAT volume was associated with HOMA2-IR (p < 0.001). Higher proportions of SAT intermediate macrophages (IMs), myofibroblasts, and MYOC + fibroblasts were associated with greater VAT volume using partial Spearman's correlation adjusting for age, sex, and body mass index (ρ=0.34-0.49, p < 0.05 for all). Whole SAT transcriptomics showed PWH with greater VAT volume have increased expression of extracellular matrix (ECM)- and inflammation-associated genes, and reduced expression of lipolysis- and fatty acid metabolism-associated genes., Conclusions: In PWH, greater VAT volume is associated with higher proportion of SAT IMs and fibroblasts, and a SAT ECM and inflammatory transcriptome, which is similar to findings in HIV-negative persons with obesity. These data identify SAT cell-type specific changes associated with VAT volume in PWH that could underlie the high rates of cardiometabolic diseases in PWH, though additional longitudinal studies are needed to define directionality and mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2024
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39. Cytokine and Chemokine Receptor Profiles in Adipose Tissue Vasculature Unravel Endothelial Cell Responses in HIV.
- Author
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Obare LM, Priest S, Ismael A, Mashayekhi M, Zhang X, Stolze LK, Sheng Q, Vue Z, Neikirk K, Beasley H, Gabriel C, Temu T, Gianella S, Mallal S, Koethe JR, Hinton A, Bailin S, and Wanjalla CN
- Abstract
Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF-α and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies., Competing Interests: Declaration of interests The authors have no competing interests.
- Published
- 2024
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40. Single cell RNA-sequencing suggests a novel lipid associated mast cell population following weight cycling.
- Author
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Caslin HL, Cottam MA, Betjemann AM, Mashayekhi M, Silver HJ, and Hasty AH
- Abstract
Our recent study showed weight cycled mice have increased adipose mast cells compared to obese mice by single cell RNA-sequencing. Here, we aimed to confirm and elucidate these changes. Further analysis of our dataset showed that our initial mast cell cluster could subcluster into two unique populations: one with very high expression of classical mast cell markers and another with elevated lipid handling and antigen presentation genes. This new mast cell cluster accounted for most of the mast cells in the weight cycled group although it was not possible to detect the different populations by new studies with flow cytometry or Toluidine blue staining in mice, possibly due to a downregulation in classical mast cell genes. Interestingly, a pilot study in humans did suggest the existence of two mast cell populations in subcutaneous adipose tissue from obese women that appear similar to the murine populations detected by sequencing; one of which was significantly correlated with weight variance. Together, these data suggest that weight cycling may induce a unique population of mast cells similar to lipid associated macrophages. Future studies will focus on isolation of these cells to better determine their lineage, differentiation, and functional roles.
- Published
- 2023
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41. CD4 + T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV.
- Author
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Wanjalla CN, Gabriel CL, Fuseini H, Bailin SS, Mashayekhi M, Simmons J, Warren CM, Glass DR, Oakes J, Gangula R, Wilfong E, Priest S, Temu T, Newell EW, Pakala S, Kalams SA, Gianella S, Smith D, Harrison DG, Mallal SA, and Koethe JR
- Subjects
- Humans, Calcium, CX3C Chemokine Receptor 1, Cytomegalovirus, Risk Factors, T-Lymphocyte Subsets, Cardiovascular Diseases, CD4-Positive T-Lymphocytes, HIV Infections
- Abstract
Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1
+ , GPR56+ , and CD57+/- T cells (termed CGC+ ) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on long-term ART. We found that PWH with cardiometabolic diseases (non-alcoholic fatty liver disease, calcified coronary arteries, or diabetes) had higher circulating CGC+ CD4+ T cells compared to metabolically healthy PWH. The traditional risk factor most correlated with CGC+ CD4+ T cell frequency was fasting blood glucose, as well as starch/sucrose metabolites. While unstimulated CGC+ CD4+ T cells, like other memory T cells, depend on oxidative phosphorylation for energy, they exhibited higher expression of carnitine palmitoyl transferase 1A compared to other CD4+ T cell subsets, suggesting a potentially greater capacity for fatty acid β-oxidation. Lastly, we show that CMV-specific T cells against multiple viral epitopes are predominantly CGC+ . Together, this study suggests that among PWH, CGC+ CD4+ T cells are frequently CMV-specific and are associated with diabetes, coronary arterial calcium, and non-alcoholic fatty liver disease. Future studies should assess whether anti-CMV therapies could reduce cardiometabolic disease risk in some individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wanjalla, Gabriel, Fuseini, Bailin, Mashayekhi, Simmons, Warren, Glass, Oakes, Gangula, Wilfong, Priest, Temu, Newell, Pakala, Kalams, Gianella, Smith, Harrison, Mallal and Koethe.)- Published
- 2023
- Full Text
- View/download PDF
42. Relationship of Subcutaneous Adipose Tissue Inflammation-Related Gene Expression With Ectopic Lipid Deposition in Persons With HIV.
- Author
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Bailin SS, Gabriel CL, Fan R, Ye F, Nair S, Terry JG, Carr JJ, Silver H, Wanjalla CN, Mashayekhi M, Lima M, Woodward B, Hannah L, Fuseini H, Ferguson JF, Kropski JA, and Koethe JR
- Subjects
- Adipose Tissue metabolism, Gene Expression, Humans, Inflammation complications, Intra-Abdominal Fat metabolism, Lipids, Subcutaneous Fat, Subcutaneous Fat, Abdominal metabolism, HIV Infections complications, HIV Infections drug therapy, HIV Infections genetics
- Abstract
Objective: Fat redistribution from subcutaneous adipose tissue (SAT) to the abdominal viscera, pericardium, liver, and skeletal muscle contributes to the rising burden of cardiometabolic disease among persons with HIV (PWH). Previous studies found SAT inflammation in PWH impairs lipid storage and persists despite plasma viral suppression on antiretroviral therapy (ART). In this study, we identified SAT immune-related genes associated with ectopic fat deposition in PWH on long-term ART., Design and Methods: A total of 92 PWH with well-controlled viremia underwent computed tomography imaging and abdominal SAT biopsy for gene expression analysis. SAT gene expression was measured using a NanoString panel of 255 immune-related genes. Associations between gene expression and computed tomography measurements of the volume and attenuation (radiodensity) of metabolically relevant ectopic fat depots were assessed using multivariable linear regression and network analysis., Results: Greater SAT volume was associated with higher visceral and pericardial adipose tissue volume, but lower skeletal muscle attenuation. Lower SAT attenuation, a measure of lipid content, was associated with lower visceral adipose tissue attenuation. Hierarchical clustering identified a subset of macrophage-related genes in SAT, including CCL2, CCL22, CCL13, CCR1, CD86, CD163, IL-6, IL-10, MRC1, and TREM2, which were associated with an increased lipid deposition in multiple ectopic depots., Conclusion: Altered expression of macrophage-related genes in SAT is associated with differences in ectopic fat depot morphometrics among PWH on long-term ART, including in the pericardial and visceral compartments. These findings provide basis for future studies to assess host, virus, and treatment factors shaping the SAT immune environment and its effects on morphometric changes and metabolic comorbidities in PWH., Competing Interests: J.R.K. has served as a consultant to Gilead Sciences, Merck, ViiV Healthcare, Janssen, and Theratechnologies and has received research support from Gilead Sciences and Merck. C.N.W. has served as a consultant to ViiV Healthcare. J.A.K. has served as a consultant for Boehringer Ingelheim, Janssen, and APIE Therapeutics, received grant support from Boehringer Ingelheim and Bristol-Meyers-Squibb, and other study support from Genentech. S.N., J.G.T., and J.J.C. receive grant support from Theratechnologies and IBM Watson. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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43. Leptin Promotes Greater Ki67 Expression in CD4 + T Cells From Obese Compared to Lean Persons Living With HIV.
- Author
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Fuseini H, Smith R, Nochowicz CH, Simmons JD, Hannah L, Wanjalla CN, Gabriel CL, Mashayekhi M, Bailin SS, Castilho JL, Hasty AH, Koethe JR, and Kalams SA
- Subjects
- Adult, Biomarkers, Body Mass Index, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Cytokines metabolism, Female, Flow Cytometry, HIV Infections virology, Humans, Ki-67 Antigen genetics, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Lymphocyte Activation, Lymphocyte Count, Male, Middle Aged, Obesity genetics, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes metabolism, Gene Expression, HIV Infections genetics, Ki-67 Antigen metabolism, Leptin pharmacology, Obesity metabolism
- Abstract
While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4
+ T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m2 , is positively correlated with greater CD4+ T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4+ T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4+ T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4+ T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4+ T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4+ T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4+ T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4+ T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4+ T reconstitution in PLWH initiating ART., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fuseini, Smith, Nochowicz, Simmons, Hannah, Wanjalla, Gabriel, Mashayekhi, Bailin, Castilho, Hasty, Koethe and Kalams.)- Published
- 2022
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- View/download PDF
44. Anticytomegalovirus CD4 + T Cells Are Associated With Subclinical Atherosclerosis in Persons With HIV.
- Author
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Wanjalla CN, Mashayekhi M, Bailin S, Gabriel CL, Meenderink LM, Temu T, Fuller DT, Guo L, Kawai K, Virmani R, Jenkins C, Abana CO, Warren CM, Gangula R, Smith R, Madhur MS, Finn AV, Gelbard AH, Su YR, Tyska MJ, Kalams SA, Harrison DG, Mallal SA, Absi TS, Beckman JA, and Koethe JR
- Subjects
- Adult, Asymptomatic Diseases, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes virology, Carotid Artery Diseases diagnostic imaging, Carotid Artery Diseases virology, Case-Control Studies, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease virology, Cross-Sectional Studies, Cytomegalovirus Infections diagnosis, Cytomegalovirus Infections virology, Epitopes, Female, HIV Infections diagnosis, HIV Infections virology, Heart Disease Risk Factors, Humans, Male, Middle Aged, Plaque, Atherosclerotic, Risk Assessment, Vasodilation, CD4-Positive T-Lymphocytes immunology, Carotid Artery Diseases immunology, Coinfection, Coronary Artery Disease immunology, Cytomegalovirus immunology, Cytomegalovirus Infections immunology, HIV Infections immunology, Viral Envelope Proteins immunology
- Abstract
[Figure: see text].
- Published
- 2021
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45. Adipose Tissue in Persons With HIV Is Enriched for CD4 + T Effector Memory and T Effector Memory RA + Cells, Which Show Higher CD69 Expression and CD57, CX3CR1, GPR56 Co-expression With Increasing Glucose Intolerance.
- Author
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Wanjalla CN, McDonnell WJ, Barnett L, Simmons JD, Furch BD, Lima MC, Woodward BO, Fan R, Fei Y, Baker PG, Ram R, Pilkinton MA, Mashayekhi M, Brown NJ, Mallal SA, Kalams SA, and Koethe JR
- Subjects
- Adult, Antigens, CD immunology, Antigens, Differentiation, T-Lymphocyte immunology, CD57 Antigens immunology, CX3C Chemokine Receptor 1 immunology, Female, Humans, Immunologic Memory immunology, Lectins, C-Type immunology, Male, Middle Aged, Receptors, G-Protein-Coupled immunology, Adipose Tissue immunology, CD4-Positive T-Lymphocytes immunology, Glucose Intolerance immunology, HIV Infections immunology, T-Lymphocyte Subsets immunology
- Abstract
Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4
+ and CD8+ T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic ( n = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic ( n = 8; FBG = 100-125 mg/dL) and diabetic ( n = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls ( n = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (TNai ) CD45RO- CCR7+ , effector memory (TEM ) CD45RO+ CCR7- , central memory (TCM ) CD45RO+ CCR7+ , and effector memory revertant RA+ (TEMRA ) CD45RO- CCR7- CD4+ and CD8+ T cells were measured by flow cytometry. CD4+ and CD8+ TEM and TEMRA were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4+ and CD8+ memory subsets were similar across metabolic status categories in the PLWH, but CD4+ T cell expression of the CD69 early-activation and tissue residence marker, particularly on TEM cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69lo TEM and TEMRA cells co-expressing CD57, CX3 CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX3 CR1 and GPR56 markers indicate these TEM and TEMRA cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4+ and CD8+ memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.- Published
- 2019
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46. Type I interferon is selectively required by dendritic cells for immune rejection of tumors.
- Author
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Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, Lee H, Arthur CD, White JM, Kalinke U, Murphy KM, and Schreiber RD
- Subjects
- Adoptive Transfer, Animals, Chimera, Cross-Priming immunology, Dendritic Cells cytology, Granulocytes immunology, Immunity, Innate immunology, Interferon-gamma immunology, Killer Cells, Natural immunology, Lymphocyte Activation immunology, Macrophages immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasms pathology, Receptor, Interferon alpha-beta genetics, Receptor, Interferon alpha-beta immunology, T-Lymphocyte Subsets immunology, T-Lymphocytes, Cytotoxic immunology, Dendritic Cells immunology, Interferon Type I immunology, Neoplasms immunology
- Abstract
Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN's actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre(+)Ifnar1(f/f) mice) cannot reject highly immunogenic tumor cells and that CD8α(+) DCs from these mice display defects in antigen cross-presentation to CD8(+) T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α(+) DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.
- Published
- 2011
- Full Text
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47. Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression.
- Author
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Albring JC, Sandau MM, Rapaport AS, Edelson BT, Satpathy A, Mashayekhi M, Lathrop SK, Hsieh CS, Stelljes M, Colonna M, Murphy TL, and Murphy KM
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Cell Line, Tumor, Listeriosis immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Receptors, Immunologic antagonists & inhibitors, Receptors, Tumor Necrosis Factor, Member 14 physiology, T-Lymphocytes, Regulatory immunology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation, Immunosuppression Therapy, Receptors, Immunologic physiology
- Abstract
Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non-life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered at the time of aHSCT. Once GVHD was established, anti-BTLA treatment was unable to reverse disease, suggesting that its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of its ligand, the costimulatory tumor necrosis factor receptor herpesvirus entry mediator (HVEM), and required BTLA expression by donor-derived T cells. Furthermore, anti-BTLA treatment led to the relative inhibition of CD4(+) forkhead box P3(-) (Foxp3(-)) effector T cell (T eff cell) expansion compared with precommitted naturally occurring donor-derived CD4(+) Foxp3(+) regulatory T cell (T reg cell) and allowed for graft-versus-tumor (GVT) effects as well as robust responses to pathogens. These results suggest that BTLA agonism rebalances T cell expansion in lymphopenic hosts after aHSCT, thereby preventing GVHD without global immunosuppression. Thus, targeting BTLA with a monoclonal antibody at the initiation of aHSCT therapy might reduce limitations imposed by histocompatibility and allow broader application to treatment of non-life-threatening diseases.
- Published
- 2010
- Full Text
- View/download PDF
48. Transplantation tolerance in NF-kappaB-impaired mice is not due to regulation but is prevented by transgenic expression of Bcl-xL.
- Author
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Zhou P, Balin SJ, Mashayekhi M, Hwang KW, Palucki DA, and Alegre ML
- Subjects
- Adoptive Transfer, Animals, CD4-Positive T-Lymphocytes immunology, Graft Rejection immunology, H-2 Antigens, Heart Transplantation immunology, I-kappa B Proteins genetics, I-kappa B Proteins immunology, Immune Tolerance, Interferon-gamma biosynthesis, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, NF-KappaB Inhibitor alpha, NF-kappa B antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 genetics, Skin Transplantation immunology, bcl-X Protein, NF-kappa B immunology, Proto-Oncogene Proteins c-bcl-2 immunology, Transplantation Immunology
- Abstract
NF-kappaB is a key regulator of transcription after TCR and costimulatory receptor ligation. To determine the role of T cell-intrinsic NF-kappaB activation in acute allograft rejection, we used IkappaBalphaDeltaN-Tg mice (H-2b) that express an inhibitor of NF-kappaB restricted to the T cell compartment. We have previously shown that these mice permanently accept fully allogeneic (H-2d) cardiac grafts and secondary donor skin grafts, and that splenocytes from these tolerant mice have reduced alloreactivity when restimulated in vitro. These results were compatible with either deletion or suppression of allospecific T cells as possible mechanisms of tolerance. The aim of this study was to investigate the mechanism of transplant tolerance in these mice. IkappaBalphaDeltaN-Tg mice did not have increased numbers or function of CD4+ CD25+ regulatory T cells either before or after cardiac transplantation. In addition, tolerance could not be transferred to fresh NF-kappaB-competent T cells and was not permissive for linked suppression to skin grafts sharing donor and third-party alloantigens, suggesting that dominant suppression is not the mechanism by which IkappaBalphaDeltaN-Tg mice achieve tolerance. In contrast, overexpression of the antiapoptotic protein Bcl-xL in T cells from IkappaBalphaDeltaN-Tg mice resulted in effective rejection of cardiac allografts and correlated with an increased frequency of splenocytes producing IFN-gamma in response to alloantigen. Together, these results suggest that the death of alloreactive T cells may be partly responsible for the transplantation tolerance observed in mice with defective T cell-intrinsic NF-kappaB activation.
- Published
- 2005
- Full Text
- View/download PDF
49. Transgenic expression of CTLA-4 controls lymphoproliferation in IL-2-deficient mice.
- Author
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Hwang KW, Sweatt WB, Mashayekhi M, Palucki DA, Sattar H, Chuang E, and Alegre ML
- Subjects
- Anemia, Hemolytic, Autoimmune genetics, Anemia, Hemolytic, Autoimmune immunology, Anemia, Hemolytic, Autoimmune prevention & control, Animals, Antigen-Presenting Cells immunology, Antigens, CD, Antigens, Differentiation physiology, CD28 Antigens physiology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes pathology, CTLA-4 Antigen, Cell Death genetics, Cell Death immunology, Growth Inhibitors biosynthesis, Growth Inhibitors genetics, Growth Inhibitors physiology, Lymphocyte Count, Mice, Mice, Knockout, Mice, Transgenic, Receptors, Interleukin-2 biosynthesis, Splenomegaly genetics, Splenomegaly immunology, Splenomegaly prevention & control, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets pathology, Antigens, Differentiation biosynthesis, Antigens, Differentiation genetics, Gene Expression Regulation immunology, Interleukin-2 deficiency, Interleukin-2 genetics, Lymphocyte Activation genetics, Transgenes immunology
- Abstract
IL-2-deficient mice develop a lymphoproliferative and autoimmune disease characterized by autoimmune hemolytic anemia (AHA) and inflammatory bowel disease. We have previously reported that IL-2 is necessary for optimal up-regulation of CTLA-4, an inducible negative regulator of T cell activation. In this study, we have tested the hypothesis that reduced expression of CTLA-4 in IL-2-deficient T cells contributes to the pathogenesis of disease in IL-2-deficient mice. Expression of CTLA-4 as a transgene completely prevented lymphoaccumulation and AHA in IL-2-deficient mice. The normalization of T cell numbers was due to inhibition of expansion of conventional CD4+CD25- T cells rather than to rescue of the numbers or function of CD4+CD25+ regulatory T cells, suggesting that CTLA-4 expression on conventional T cells plays a role in maintaining normal T cell homeostasis. In addition, the inhibitory effect of the CTLA-4 transgene on T cell expansion was at least in part independent of CD28 expression. Our results suggest that deficient CTLA-4 expression on conventional T cells contributes to the pathophysiology of the lymphoproliferative disease and AHA in IL-2-deficient mice. Thus, restoring CTLA-4 expression in T cells may be an attractive strategy to control clinical autoimmune diseases in which CTLA-4 expression is reduced.
- Published
- 2004
- Full Text
- View/download PDF
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