Inflammatory and immunomodulatory regulatory mechanisms in benign prostatic hyperplasia

2.1 Immune cells in chronic inflammation

In healthy prostatic tissue, a small number of lymphocytes can be observed in the glandular epithelium and around the ducts. T lymphocytes account for more than 90% of these infiltrating cells and are predominantly of the Cluster of Differentiation 8+ (CD8+) subtype, accompanied by a small number of macrophages. In the fibromuscular stroma, lymphoid aggregates are present, consisting of a central core containing 60% B lymphocytes and a surrounding parafollicular area composed of 40% T lymphocytes, mainly of the CD4+ subtype [7]. Conversely, in prostate tissues with chronic inflammation, T lymphocytes are markedly increased and are predominantly of the CD4+ subtype. In addition, approximately 30% of other inflammatory cells, including B lymphocytes, macrophages, and mast cells, infiltrate the glands, periglandular areas, and stromal compartments. The composition and distribution of these immune cells differ substantially from those observed in healthy prostate tissue [4]. Aberrant infiltration of inflammatory cells indicates disruption of local immune homeostasis and may contribute to the development and progression of BPH.

Macrophages play an important role in the progression of prostatic hyperplasia. They not only promote proliferation of prostatic epithelial cells by secreting cytokines that activate the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways [8], but also regulate the expression of the androgen receptor (AR) and CD40/CD40L through activation of the mitogen-activated protein kinase (MAPK) pathway, thereby promoting inflammation and cellular proliferation while inhibiting apoptosis in BPH tissues [9]. Macrophages are broadly classified into M1 macrophages (classically activated macrophages) and M2 macrophages (alternatively activated macrophages). M1 macrophages mainly secrete pro-inflammatory mediators during the early phase of inflammation, whereas M2 macrophages contribute to the suppression of inflammation and tissue repair through phagocytosis, as well as pro-angiogenic and pro-fibrotic phenotypes. M2 macrophages are the predominant inflammatory cells infiltrating BPH tissues and driving prostatic-cell proliferation, largely through secretion of cytokines and growth factors involved in disease progression [10]. Among these, the M2a subtype appears to be particularly important and may promote BPH progression by increasing expression of insulin-like growth factor 1 (IGF-1) [11]. Lanman et al. [12] reported that lipid-rich macrophage subpopulations accumulate in enlarged prostates and are positively associated with LUTS severity. Collectively, these findings support a multifaceted role of macrophages in BPH, although the precise mechanisms remain to be fully clarified.

Overall, immune-cell infiltration in BPH should not be regarded merely as a histological observation, but rather as an active component of a self-sustaining inflammatory microenvironment.

2.2 Cytokine network in the BPH microenvironment

The inflammatory microenvironment in BPH is shaped by a complex network of cytokines and chemokines, rather than by a single mediator. These inflammatory signals act in concert to promote immune-cell recruitment, aberrant remodeling of prostatic tissue, and disease progression. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that supports the growth of both epithelial and stromal cells. As a key mediator of paracrine and autocrine signaling, IL-6 promotes cellular proliferation and survival, thereby contributing to prostatic hyperplasia [13]. Elevated IL-6 levels are associated with increased prostate volume and more severe LUTS [14], suggesting that IL-6 may link inflammation to hyperplastic growth in BPH. Interleukin-8 (IL-8) is considered one of the most important cytokines involved in the initiation and progression of BPH and can directly stimulate proliferation of prostatic epithelial and stromal cells [15]. Compared with normal prostate tissue, the levels of IL-8 and its receptors are increased by 5- to 25-fold in BPH tissues, and gene-editing studies have further confirmed that the IL-8 axis directly promotes prostatic epithelial-cell growth [16]. In addition, IL-8 has been proposed as one of the most reliable indicators of prostatic inflammation, including chronic prostatitis and chronic pelvic pain syndrome/BPH, and is closely associated with IPSS and prostate-specific antigen (PSA) levels in patients with BPH [17]. Tumor necrosis factor alpha (TNF-α) is a key mediator of both systemic and local inflammation and promotes immune-cell activation and the production of inflammatory mediators. Elevated TNF-α levels are associated with increased tissue remodeling, fibrosis, and smooth muscle-cell proliferation in the prostate. TNF-α protein expression is significantly higher in patients with larger prostates than in those with smaller prostates [18], and clinical studies have shown a negative association between TNF-α inhibitor use and prostate growth rate [19]. In addition to IL-6, IL-8, and TNF-α, the IL-1 family, transforming growth factor beta (TGF-β), and various chemokines also contribute to BPH. Interleukin-1 beta (IL-1β) modulates immune responses and promotes fibrosis, whereas TGF-β supports stromal hyperplasia. Together, these mediators maintain a chronic inflammatory milieu in the prostate and drive tissue remodeling and disease progression [15]. Through extensive cross-talk, cytokines and chemokines sustain immune-cell recruitment, oxidative stress, and extracellular matrix remodeling. Such interactions amplify the inflammatory response and contribute to persistent tissue injury in BPH. In summary, cytokine dysregulation in BPH reflects a coordinated inflammatory network that drives tissue remodeling and disease heterogeneity, thereby providing new opportunities for immune-targeted therapeutic intervention.

3.1 NF-κB signaling pathway

The nuclear factor kappa B (NF-κB) signaling pathway is a central regulatory axis in BPH-associated inflammation. Inflammatory cytokines such as TNF-α and IL-1β, as well as oxidative stress, metabolic disturbances, and microbe-related stimuli, can all activate NF-κB. Activated NF-κB subsequently induces downstream inflammatory mediators, including cyclooxygenase-2 (COX-2), while enhancing anti-apoptotic and pro-proliferative signaling, thereby promoting persistent inflammation, increased cell survival, and abnormal proliferation within prostatic tissue [20]. Interactions between infiltrating immune cells and local prostatic epithelial and stromal cells may further amplify this process, leading to sustained chronic inflammation, stromal hyperplasia, and tissue remodeling. Thus, NF-κB mediates not only the inflammatory response itself, but also the molecular processes through which inflammation is translated into a hyperplastic phenotype. Clinical studies also suggest that NF-κB activation is associated with the degree of tissue hyperplasia in BPH. Immunohistochemical analyses of prostate tissues from 101 patients with BPH showed that NF-κB is expressed in both glandular and stromal compartments and that patients showing NF-κB activation have larger prostate volumes [21]. In addition, testosterone propionate may exacerbate prostatic inflammation and cellular proliferation through activation of the NF-κB pathway [22]. Together, these findings suggest that aberrant NF-κB activation contributes to persistent inflammation and prostatic remodeling in BPH. Based on these mechanisms, NF-κB is considered a potential anti-inflammatory therapeutic target. Experimental studies have shown that several natural compounds, such as extracts of Celtis choseniana Nakai and resveratrol, can attenuate inflammatory responses and inhibit prostatic-cell proliferation by suppressing NF-κB-related signaling [23, 24]. However, because NF-κB is broadly involved in physiological immune regulation, the specificity, long-term safety, and clinical translational value of NF-κB-targeted therapy in BPH require further investigation. NF-κB may represent a key converging node linking multiple inflammatory stimuli to persistent prostatic remodeling.

3.2 NLRP3 inflammasome

As a key amplifier of inflammatory signaling, the inflammasome has attracted considerable attention, particularly the NLR family pyrin domain containing 3 (NLRP3) inflammasome, an intracellular multiprotein cytoplasmic complex that belongs to the innate immune system. Studies have shown that complement component C5a activates the NLRP3 inflammasome, thereby promoting caspase-1-dependent production of IL-1β and IL-18 and contributing to stromal proliferation in BPH [25]. NLRP3 may originate from prostatic stromal cells, especially myofibroblasts. Wang et al. [26] also demonstrated, by immunohistochemical analysis, that NLRP3 inflammasome expression is significantly higher in BPH tissues than in healthy prostate tissue and further confirmed that modulation of the NLRP3 inflammasome can attenuate inflammation and oxidative-stress injury in BPH. Inhibition of the NLRP3 inflammasome by resveratrol has been shown to reduce prostate volume. In addition, resveratrol and the antioxidant mitoquinone may slow BPH progression by suppressing NLRP3-related signaling pathways [25, 27]. Therefore, NLRP3 may represent a critical node linking inflammatory amplification to persistent prostatic remodeling, although the current evidence still requires confirmation in larger studies with stronger clinical relevance.

3.3 Th17/IL-17 axis

Adaptive immune dysregulation also contributes to the maintenance of the inflammatory microenvironment in BPH-associated chronic inflammation. In recent years, the imbalance between T helper 17 (Th17) cells and regulatory T (Treg) cells has attracted considerable attention. Th17 cells are characterized by secretion of IL-17, which promotes neutrophil recruitment and amplifies local inflammatory responses, whereas Treg cells primarily mediate immunosuppression and maintain immune tolerance and inflammatory balance. Disruption of this dynamic equilibrium may drive the transition of local prostatic inflammation from a transient response to a persistent chronic inflammatory state. Previous studies have shown that, compared with normal prostate tissue, BPH tissues exhibit increased Th17-cell infiltration and overexpression of IL-17A mRNA [28, 29]. IL-17 not only participates in inflammatory-cell recruitment, but also induces the release of additional pro-inflammatory cytokines and chemokines, thereby enhancing cytokine cascades and sustaining chronic tissue inflammation. In the context of BPH, IL-17-related responses may not only reflect local inflammatory activation, but also contribute to hyperplastic progression by strengthening epithelial-stromal interactions and amplifying pro-inflammatory signaling. Radej et al. [30] isolated Propionibacterium acnes from BPH and PCa tissues and proposed that this bacterium may stimulate malignant-cell proliferation by inducing IL-17 secretion from Th17 cells, while also promoting the formation of an inflammatory microenvironment through disruption of Th17/Treg balance, thereby contributing to both BPH and PCa development [31]. Th17/Treg imbalance may also link BPH to other inflammatory prostatic disorders. Current evidence suggests that this immune dysregulation is observed not only in BPH, but also in chronic prostatitis- and chronic pelvic pain syndrome-associated inflammatory settings, indicating the existence of partially overlapping inflammatory phenotypes among different prostatic diseases [32]. Peripheral-blood studies also support this trend, showing that the proportion of Th17 cells and the Th17/Treg ratio are elevated in patients with BPH compared with healthy controls [33]. This finding suggests that the imbalance may not be confined to local tissue, but may also reflect a systemic inflammatory bias. Nevertheless, current evidence mainly indicates an association between Th17/Treg abnormalities and BPH-related inflammation. Their precise role in different clinical phenotypes of BPH, their utility as stable prognostic biomarkers, and their similarities to or differences from the inflammatory microenvironment of prostate cancer all require further study.

Overall, current evidence suggests that the Th17/IL-17 axis and Th17/Treg imbalance may participate in maintaining chronic inflammation in BPH and promote local tissue remodeling through the inflammation-amplifying effects of IL-17. However, the specific contribution of this immune axis to different BPH phenotypes has not yet been fully defined.

3.4 TGF-β

Transforming growth factor beta (TGF-β) is a multifunctional polypeptide cytokine that plays important roles in BPH progression by promoting epithelial-mesenchymal transition (EMT), prostatic fibrosis, and inflammation, and is considered one of the most active regulators driving disease progression and symptom development. Binding of TGF-β to its receptors activates Smad signaling, which induces fibroblast differentiation into myofibroblasts, promotes extracellular-matrix formation and deposition, and ultimately leads to fibrosis [34]. At the same time, TGF-β may further aggravate TGF-β-induced fibrosis by promoting the production of inflammatory mediators such as IL-6 and TNF-α through downstream NF-κB signaling and by inducing oxidative stress. Wang et al. [35] found that TGF-β1 can also impair the epithelial barrier of the prostate by downregulating the tight-junction protein claudin-1 via the Mitogen activated protein kinase kinase (MEK)/Extracellular signal-regulated kinase (ERK) pathway. Blockade of TGF-β signaling has been considered an effective therapeutic strategy in multiple diseases and has also attracted attention in BPH research. For example, neferine can alleviate BPH progression by inhibiting TGF-β-mediated EMT and oxidative stress [36], whereas hesperidin improves BPH by modulating the TGF-β/Smad signaling pathway, thereby attenuating cellular proliferation, inflammation, and EMT [37]. These findings suggest a promising therapeutic avenue for BPH.

Collectively, these pathways should not be interpreted as isolated molecular events. Instead, they form an interconnected signaling network through which inflammatory stimuli are translated into persistent proliferation, remodeling, and clinical progression.

4.1 Metabolic syndrome and inflammation

Metabolic syndrome (MetS) is not a single disease, but rather a cluster of coexisting and interrelated metabolic abnormalities, including central obesity, hypertension, elevated fasting glucose, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol (HDL-C). Growing evidence suggests that MetS is not only an important background factor for cardiovascular disease and diabetes, but may also provide a systemic inflammatory basis for the development and progression of BPH/LUTS. Epidemiological studies have shown that older Chinese men with MetS have a 1.60-fold higher risk of developing BPH/LUTS than those without MetS, and this association is particularly evident for low HDL, abdominal obesity, elevated triglycerides, and hyperglycemia [38]. Meanwhile, multiple studies have demonstrated associations between MetS and increased prostate volume as well as progression of LUTS, with inflammation serving as a central mediating mechanism. Prostatic inflammation is negatively correlated with heme oxygenase-1 and HDL levels in prostatic tissue and positively correlated with triglyceride levels [39]. Patients with BPH complicated by MetS exhibit significantly higher immunoexpression of IL-6 and IL-18 in prostatic tissue than patients with BPH alone [13]. Gacci et al. [40] reported that patients with both MetS and BPH have significantly higher grades of prostatic inflammation than those without MetS, and that elevated serum triglycerides and lower HDL-C levels are associated with an increased risk of prostate volume ≥60 mL. Diverse pathogenic pathways contributing to MetS ultimately converge on a state of chronic low-grade inflammation, leading to elevated inflammatory markers such as C-reactive protein (CRP) and pro-inflammatory cytokines including IL-8 and IL-6. This chronic inflammation induces tissue injury and repetitive wound-healing responses, ultimately promoting the development of BPH [41, 42]. Insulin and insulin-like growth factor 1 (IGF-1) can inactivate the alpha and beta subunits of glycogen synthase kinase-3 through phosphorylation, thereby increasing the expression of IL-17-induced inflammatory cytokines and chemokines and ultimately amplifying intraprostatic inflammation [43]. In obesity-induced inflammation, aberrant secretion of inflammatory cytokines and chemokines can also accelerate inflammatory progression within the prostate. An animal study showed that excessive fat intake activates signal transducer and activator of transcription 3 (STAT3) and NF-κB in the prostate, increases IL-6 expression, and aggravates intraprostatic inflammation [44], whereas caloric restriction reduces immune-inflammatory infiltration and tissue remodeling in rat prostate tissue [45]. Overall, the association between MetS and BPH is biologically plausible and is increasingly supported by both clinical and experimental evidence. However, because the components of MetS frequently cluster with aging and other comorbidities, the causal relationship between MetS and BPH remains difficult to fully disentangle. MetS may promote BPH/LUTS progression through systemic low-grade inflammation, dysregulated metabolic signaling, and local tissue remodeling, but the magnitude of this effect and its contribution to different BPH phenotypes still require further clarification.

4.2 Microbial community and inflammation