Biology subjects

Mashayekhi, M.

Publications and source records attributed to Mashayekhi, M..

6 recordsLinked to original sources

bioRxiv2026

Adipose tissue as a site of immune activation and dysfunction in individuals with obesity and asthma

Obesity increases local inflammatory responses in adipose tissue. Individuals with obesity have increased asthma incidence and severity and reduced responses to asthma therapeutics through unknown mechanisms. To identify mechanisms by which increased fat mass augments asthma pathogenesis, single cell RNA sequencing of the immune-rich stromovascular fraction of subcutaneous adipose tissue was conducted from well-characterized adults with obesity-associated asthma matched to adults without asthma. Individuals with asthma had increased abundance of perivascular macrophages and lymphoid-associated macrophages (LAMs) and reduced abundance of classical monocytes and CD4+ and CD8+ naive T cells. Pseudo-bulk differential expression (DE) identified upregulation of cellular metabolism, specifically oxidative phosphorylation, and decreased immune homeostatic pathways in asthma across immune cell subsets. Cell type specific DE analysis of effector cell subtypes identified significant induction of metallothionein gene expression in asthma, a signature of immune cell dysfunction characterized by both an activation and exhaustion phenotype. Gene co-expression analysis identified gene modules associated with asthma diagnosis, lung function, and biomarkers of type 2 inflammation were enriched in effector cells. These data identify adipose tissue dysfunction occurs in obesity-associated asthma and support adipose tissue as therapeutic target to address the enhanced asthma risk among those with obesity. Grant SupportNIH U01AI155299, P30DK020593, R01AI182159, K23HL159351, UL1RR024975-03, P30CA68485, P30EY08126, G20RR030956, 5UL1TR002243, KL2TR002245, P30AI110527, DK020593, American Heart Association 17SFRN33520017.

immunology↗

bioRxiv2024

Cytokine and Chemokine Receptor Profiles in Adipose Tissue Vasculature Unravel Endothelial Cell Responses in HIV

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- 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.

cell biology↗

bioRxiv2023

Single cell RNA-sequencing suggests a novel lipid associated mast cell population following weight cycling

We previously demonstrated that 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. Interestingly, we did not detect an increase in total mast cell numbers in weight cycled mice by Toluidine blue or flow cytometry, however, further subcluster analysis of our dataset showed that our initial mast cell cluster consisted of two unique populations. One population had very high expression of classical mast cell markers and another had elevated lipid handling and antigen presentation genes with a concomitant reduction in classical mast cell genes. This new "lipid-associated" mast cell cluster accounted for most of the mast cells in the weight cycled group. We induced a similar phenotype in vitro using repeated exposure to adipose tissue conditioned media to mimic weight gain and weight regain. Upon repeated exposure to adipose tissue conditioned media, bone marrow-derived mast cells had increased lipid droplets and reduced expression of cKit and Fc{varepsilon}R1 compared to control cells. Moreover, we analyzed mast cells in a pilot study of subcutaneous adipose tissue from four obese, prediabetic women. We found two mast cell populations that appear similar to the murine populations detected by sequencing. The population with reduced cKit and Fc{varepsilon}R1 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, which have been shown to play a role in diverse diseases from obesity and atherosclerosis to Alzheimers disease. Future studies will focus on isolation of these cells from mice and humans to better determine their lineage, differentiation, and functional roles.

immunology↗

bioRxiv2023

Distinct blood CD3+ CD14+ T Cell-Monocyte complexes harbor HIV and are dynamic, glucose-dependent, and increased in individuals with glucose intolerance

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 cell-monocyte cell-cell complexes to developing immune-mediated diseases, including HIV and diabetes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/538020v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@fdc324org.highwire.dtl.DTLVardef@168fc4org.highwire.dtl.DTLVardef@138a9a0org.highwire.dtl.DTLVardef@1087108_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICirculating CD3+ CD14+ T cell-monocyte complexes are higher in individuals with diabetes. C_LIO_LICD3+ CD14+ T cell-monocytes complexes comprise a heterogenous group of functional and dynamic cell-cell interactions. C_LIO_LIThe proportion of CD3+ CD14+ T cell-monocyte complexes is positively associated with fasting blood glucose and negatively with plasma IL-10 levels and CD4+ T regulatory cells. C_LIO_LICD3+ CD14+ T cell-monocyte complexes are metabolically flexible and can utilize both glycolysis and oxidative phosphorylation for their energy requirements. C_LIO_LIIn persons with treated HIV, CD3+ CD14+ T cell-monocytes have more detectable HIV DNA than circulating CD4+ T cells alone. C_LI

immunology↗

bioRxiv2022

A Single-Cell Molecular Atlas of White Adipose Tissue Shows Differences in Myeloid and Lymphoid Cell Polarization in Type 2 Diabetes and HIV Infection

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. We generated a comprehensive SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH with a spectrum of metabolic health. Glucose intolerance was associated with increased lipid-associated macrophages and 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. Many of these findings were present in a separate group of 32 diabetic HIV-negative persons, suggesting these changes are not specific to HIV.

immunology↗

bioRxiv2020

Digital spatial profiling of coronary plaques from persons living with HIV reveals high levels of STING and CD163 in macrophage enriched regions

BackgroundChronic innate and adaptive immune activation may contribute to high prevalence of cardiovascular disease in persons living with HIV (PLWH). MethodsWe assessed coronary plaques from deceased PLWH (n=6) and HIV-negative (n=6) persons matched by age and gender. Formalin-fixed, paraffin-embedded 5m thick sections were processed using Movat, hematoxylin and eosin, immunohistochemical and immunofluorescence stains. Immune cell populations were measured using surface antibodies, and immune-related protein expression from macrophage rich, T-cell rich and perivascular adipose tissue regions using GeoMx(R) digital spatial profiling. ResultsCoronary plaques from PLWH and HIV-negative persons had similar plaque area and percent stenosis. Percent CD163+ cells as measured by immunohistochemical staining was significantly higher in PLWH, median 0.29% (IQR 0.11-0.90) vs. 0.01% (IQR 0.0013-0.11) in HIV-negative plaque, p = 0.02 (Figure 1A). Other surface markers of innate cells (CD68 +, p=0.18), adaptive immune cells (CD3+, p=0.39; CD4+, p=0.09; CD8+, p=0.18) and immune trafficking markers (CX3CR1+, p=0.09) within the coronary plaque trended higher in HIV-positive plaques but did not reach statistical significance. GeoMx(R) digital spatial profiling showed higher differential protein expression of CD163 (scavenger receptor for hemoglobin-haptoglobin complex), stimulator of interferon gamma (STING, a cytosolic DNA sensor), CD25 and granzyme-B in the HIV-positive compared to HIV-negative, p<0.05(Figure 1B). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/221325v1_fig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1a4757forg.highwire.dtl.DTLVardef@1e2236org.highwire.dtl.DTLVardef@582f4borg.highwire.dtl.DTLVardef@188f376_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Characterization of coronary plaques. Representative coronary plaques from three HIV-positive and three HIV-negative individuals were stained with H&E and Movat stain (A). Plaque area (m2) and % plaque stenosis were measured and calculated in 6 individuals per group (B). Statistical analysis, Mann-Whitney; ns not significant C_FIG ConclusionsIncreased inflammation within the coronary plaques of PLWH is characterized by more innate and adaptive immune cells. Higher STING expression in PLWH suggests that immune response to viral antigens within the plaque might be a driver above other stimulants. STING inhibitors are available and could be investigated as a future therapeutic target in PWH if these results are replicated with a larger number of plaques. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/221325v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@27fa00org.highwire.dtl.DTLVardef@8e4a65org.highwire.dtl.DTLVardef@1b65320org.highwire.dtl.DTLVardef@10b7c9a_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIImmunohistochemical and fluorescent stains combined with GeoMx(R) digital spatial profiling allowed for deep characterization of immune cells within intact coronary plaques and perivascular adipose tissue C_LIO_LICoronary plaques from HIV-positive persons had higher proportion of CD163+ immune cells compared to HIV-negative persons C_LIO_LIDifferential protein expression of immune-rich regions of interest within intact 5m sections of coronary plaques revealed higher levels of stimulator of interferon gamma (STING) in HIV-positive persons C_LI

immunology↗