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

Vickman, R. E.; Aaron-Brooks, L.; Zhang, R.; Lanman, N. A.; Lapin, B.; Gil, V.; Greenberg, M.; Sasaki, T.; Cresswell, G. M.; Broman, M. M.; Petkewicz, J.; Talaty, P.; Helfand, B. T.; Glaser, A. P.; Wang, C.-H.; Franco, O. E.; Ratliff, T. L.; Nastiuk, K. L.; Crawford, S. E.; Hayward, S. W.

doi:10.1101/2021.03.11.434972

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bioRxiv · 10.1101/2021.03.11.434972

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

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Abstract

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.

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Vickman, R. E., Aaron-Brooks, L., Zhang, R., Lanman, N. A., Lapin, B., Gil, V., Greenberg, M., Sasaki, T., Cresswell, G. M., Broman, M. M., Petkewicz, J., Talaty, P., Helfand, B. T., Glaser, A. P., Wang, C.-H., Franco, O. E., Ratliff, T. L., Nastiuk, K. L., Crawford, S. E., Hayward, S. W.. 2021-03-12. TNF Blockade Reduces Prostatic Hyperplasia and Inflammation while Limiting BPH Diagnosis in Patients with Autoimmune Disease. https://doi.org/10.1101/2021.03.11.434972

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