The autophagy-exosome axis in chronic prostatitis/chronic pelvic pain syndrome: a hypothesis-driven narrative review

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a debilitating condition of the urogenital system, with an elusive and multifactorial pathogenesis. Recent data show that there is a potential interplay between dysregulated autophagy and altered exosomal communication that may contribute to the persistent inflammation and pain characteristic of CP/CPPS. This review synthesizes recent advances to propose a hypothetical model: cellular stress in the prostate may trigger dysfunctional autophagy, which could reprogram secreted exosomes biogenesis and cargo in a series of lipid-raft microdomain-involved mechanisms and secretory autophagy. The outcomes of this process include the release of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) enriched exosomes, damage-associated molecular patterns (DAMPs), microRNAs (e.g., miR-155), and fibrotic mediators (e.g., TGF-β1). These signalosomes are hypothesized to transmit the inflammatory and nociceptive signals and may contribute to coordinating the dysregulation of immune cells (such as the M1 polarization of macrophages), sensitization of neurons, and tissue fibrosis, thereby potentially perpetuating the presence of a chronic disease. We critically assess the available evidence based on human studies, animal models, and in vitro systems, but recognize that there is a present requirement for additional CP/CPPS-specific mechanistic evidence. Furthermore, we explore the translational implications of this axis, discussing its promise for yielding novel exosome-based diagnostic biomarkers and its potential as a therapeutic target, while also highlighting the significant preclinical challenges and risks that must be overcome. Ultimately, the autophagy-exosome axis presents a new, integrative concept of CP/CPPS, which shifts the paradigm to the mechanisms of intercellular communication and provides new possibilities to carry out mechanism-selective research and future treatment options.