Biology subjects

Glaser, A. P.

Publications and source records attributed to Glaser, A. P..

5 recordsLinked to original sources

bioRxiv2025

Immune dysregulation in the prostates of C57BL/6Aire-/- mice mirrors that seen in human benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is the most common urologic disease in aging men, resulting in significant morbidity. The etiologies of BPH are unknown, though chronic prostatic inflammation is known to promote hyperplasia, fibrotic remodeling, and therapeutic resistance in BPH. BPH is highly complex and heterogeneous, presenting with varying degrees of stromal and epithelial proliferation, fibrosis, inflammation and associated lower urinary tract symptoms. This complexity presents challenges in developing models. Here, we characterize an Airetranscription factor-deficient non-resolving (chronic) inflammation model in a C57BL/6J background for the study of the prostatic inflammation present in BPH. This chronic inflammatory model exhibits a lack of central tolerance but retains an otherwise intact and functional immune system. C57BL/6Aire-/-mice were subcutaneously injected with prostate homogenate protein and Freunds Complete Adjuvant and boosted after 10 days. After 21 and 35 days, whole prostates were collected for histology, flow cytometry, and scRNA-seq, which were then compared to human BPH scRNA-seq data Inflammation was confined to the prostate in C57BL/6Aire-/-mice. Histological and scRNA-seq data show that the dominant leukocyte phenotypes in the prostates of C57BL/6Aire-/-mice are B and T lymphocytes. Macrophages in C57BL/6Aire-/-mouse prostates express signatures associated with an array of phenotypes as also seen in BPH. We identify a Trem2+population of macrophages, and aging-associated Cd8+GZMKhi GZMBlow T cells in C57BL/6Aire-/-prostates similar to those seen in human BPH. Further, fibroblast clusters in C57BL/6Aire-/-are similar to fibroblasts identified from the prostates of patients diagnosed with BPH, and these clusters also express markers associated with aging. Overall, the inflammation and predicted interactions between leukocytes and stromal cells observed in the prostates of C57BL/6Aire-/-mice resemble human BPH, making this model useful for studying the impact of inflammation-driven prostatic hyperplasia.

immunology↗

bioRxiv2024

Immune cell single-cell RNA sequencing analyses link an age-associated T cell subset to symptomatic benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is among the most common age-associated diseases in men; however, the contribution of age-related changes in immune cells to BPH is not clear. The current study determined that an age-associated CD8+ T cell subset (Taa) with high Granzyme K (GZMKhi) and low Granzyme B (GZMBlow) gene expression infiltrate aged human prostates and positively correlate with International Prostate Symptom Score (IPSS). A velocity analysis indicated that CD8+ T cell differentiation is altered in large BPH prostates compared to small age-matched prostates, favoring Taa accumulation. In vitro granzyme K treatment of human BPH patient-derived large prostate fibroblasts increased secretion of pro-inflammatory senescence-associated secretory phenotype (SASP)-associated cytokines. These data suggest that granzyme K-mediated stimulation of prostate stromal fibroblast SASP cytokine and chemokine production promotes prostate immune cell recruitment and activation. Overall, these results connect symptomatic BPH with immune aging.

immunology↗

bioRxiv2024

Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia

Macrophages exhibit marked phenotypic heterogeneity within and across disease states, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia. Single-cell RNA-seq of CD45+ transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes. BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, significantly accumulate with increased prostate volume. TREM2+ and MARCO+ macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2+ macrophages have significantly higher neutral lipid than TREM2- macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages. These data define two new BPH immune subpopulations, TREM2+ and MARCO+ macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.

immunology↗

bioRxiv2021

TNF Blockade Reduces Prostatic Hyperplasia and Inflammation while Limiting BPH Diagnosis in Patients with Autoimmune Disease

Benign prostatic hyperplasia (BPH) is ostensibly linked to autoimmune (AI) diseases, but whether the prostate is a target of systemic inflammation associated with AI conditions is unknown. Prostatic inflammation is linked to fibrosis, hyperplasia, and reduced responses to BPH-related medical therapies. This study was conducted to determine if AI disease correlates with BPH diagnosis and whether systemic targeting of an inflammatory mediator limits prostatic inflammation and hyperplasia. Patient medical records (n=112,152) were evaluated to determine BPH prevalence among different AI diseases. Inflammatory cells from human BPH tissues were analyzed by single-cell (sc)RNA-seq and the tumor necrosis factor (TNF)-antagonist etanercept was tested in two murine models of prostatic enlargement. BPH prevalence was significantly higher among patients with AI disease compared to unaffected individuals. However, AI patients treated with TNF-antagonists had a significantly reduced incidence of BPH. Data from scRNA- seq identified macrophages as a dominant source of TNF and in vitro assays confirmed that TNF stimulates BPH-derived fibroblast proliferation. In the AI patient cohort and murine models, systemic treatment with TNF-antagonists decreased prostatic epithelial proliferation, macrophage infiltration, and epithelial NF{kappa}B activation compared to control tissues. These studies are the first to show that patients with AI diseases have a heightened susceptibility to BPH and that the TNF-signaling axis is important for BPH pathogenesis. Macrophage-secreted TNF may mechanistically drive BPH via chronic activation of the signaling axis and NF{kappa}B. TNF blockade appears to be a promising new pharmacological approach to target inflammation and suppress BPH. One sentence summaryPatient data and mouse models suggest that repurposing tumor necrosis factor alpha blockade reduces inflammation-mediated prostatic hyperplasia.

cell biology↗

bioRxiv2017

APOBEC-Mediated Mutagenesis In Urothelial Carcinoma Is Associated With Improved Survival, Mutations In DNA Damage Response Genes, And Immune Response

BackgroundThe APOBEC family of enzymes is responsible for a mutation signature characterized by a TCW>T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival. We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and associated with higher expression of genes related to activation of the immune system.\n\nMethodsGene expression (n=408) and mutational (n=395) data from the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma provisional dataset was utilized for analysis. Tumors were split into \"APOBEC-high\" and \"APOBEC-low\" tumors based on APOBEC enrichment score. Analysis was performed with R.\n\nFindingsPatients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs 18.5 months, p=0.005). Tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2), and chromatin regulatory genes (MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with total mutational burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis and enrichment is associated with increased expression of immune-related genes, including interferon signaling.\n\nInterpretationTumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, potentially providing more single-strand DNA substrate for APOBEC3A and APOBEC3B, leading to a hypermutational phenotype and the subsequent immune response.\n\nHighlightsO_LIABPOEC enzymes, particularly APOBEC3A and APOBEC3B, are responsible for the predominant pattern of mutagenesis in bladder cancer\nC_LIO_LITumors enriched for APOBEC-mediated mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, while tumors not enriched for APOBEC-mediated mutagenesis are more likely to have mutations in KRAS and FGFR3\nC_LIO_LIAPOBEC enrichment is associated with upregulation of genes involved in the immune response\nC_LI

cancer biology↗