Lipid-rich TREM2+ macrophages: a targetable promoter of benign prostatic hyperplasia

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Endeavor Health Clinical Operations $529,928 on May 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate lipid-rich TREM2-expressing macrophages as a therapeutic target in benign prostatic hyperplasia.

The research examines mechanisms by which lipid-accumulating macrophages promote prostatic growth and lower urinary tract symptoms. The study hypothesizes that TREM2+ macrophages accumulate lipids through upregulation of oxidized LDL receptor CD36 and alterations in lipogenesis and lipolysis, and that this lipid accumulation reduces production of the anti-inflammatory protein thrombospondin-1 (TSP1), contributing to disease progression. Preliminary data show that primary TREM2+ macrophages increase lipid levels and size in prostatic epithelial spheroids compared to TREM2- macrophages, and that TREM2-knockout mice do not develop voiding dysfunction induced by steroid hormone imbalance, implicating TREM2+ macrophages in lower urinary tract symptom development.

Work is performed in Evanston, Illinois. The period of performance extends through March 31, 2031.

Abstract

Benign prostatic hyperplasia (BPH) is a common disease in aging men resulting in lower urinary tract symptoms (luts). Chronic inflammation is clearly associated with BPH and some have hypothesized that inflammatory signals can directly stimulate prostatic hyperplasia, but defined mechanisms are limited. Our group demonstrated that treatment with systemic TNF-antagonists decreases prostatic hyperplasia and macrophage (Mɸ) infiltration in humans and mouse models. We recently discovered that lipid-rich triggering receptor expressed on myeloid cells 2 (TREM2)-expressing MɸS accumulate in BPH as prostate size increases and luts worsen, suggesting that this subpopulation could be a new, specific therapeutic target. The mechanisms responsible for lipid accumulation in TREM2+ MɸS and their role in prostatic growth are unclear. Our preliminary data indicate that primary TREM2+ MɸS increase the lipid level and size of prostatic epithelial spheroids compared to TREM2- MΦS. Additionally, voiding dysfunction induced by steroid hormone imbalance in C57BL/6J mice does not occur in TREM2-/- mice, implicating an important role for TREM2+ MɸS in developing luts. TREM2+ MɸS may have altered functions due to lipid-accumulation, which we postulate is due to upregulation of oxidized LDL receptor CD36 and alterations in lipogenesis (lipid formation) and lipolysis (lipid breakdown) resulting in a net-gain of neutral lipid, often stored as lipid droplets. We determined that lipid-rich MɸS have decreased production of the anti-inflammatory protein thrombospondin-1 (TSP1), which may contribute to the global loss of TSP1 protein known to occur in human BPH. TNF-antagonist treatment in NOD mice restores TSP1 expression in the prostate, suggesting previously unrecognized signaling crosstalk between TSP1 and TNF. Loss of TSP1 and increases in TNF occur in the microenvironment as BPH progresses. We hypothesize that TREM2+ MɸS increase intracellular neutral lipid via CD36-mediated lipid-uptake, contributing to the loss of TSP1 and the increase in Mɸ-derived lipid energy fuels epithelial and stromal proliferation in a TNF-high BPH environment. Moreover, we predict that treatment with a novel ligand-independent TREM2 inhibitor or a TSP1 mimetic will reduce inflammation and epithelial proliferation to suppress BPH in animal models. The aims of this proposal are to 1) define the mechanisms contributing to the accumulation of neutral lipid in TREM2+ macrophages and the functional consequences of macrophages enriched with lipid, 2) determine how TREM2+ macrophages directly or indirectly promote prostate epithelial and stromal cell proliferation, and 3) evaluate if inhibiting TREM2 signaling or restoring TSP1 via systemic peptides can decrease lipid-rich TREM2+ macrophage abundance and decrease proliferation/symptoms in BPH models. Our research team brings expertise in prostate biology, BPH inflammation, lipid metabolism, pathology, and EX vivo tissue explant culture. These studies will provide a mechanistic understanding of how MΦS contribute to BPH and identify novel therapeutic options for inflammation-mediated prostatic hyperplasia.