Stage-dependent shifts in peritoneal cytokine profiles drive monocyte functional reprogramming in endometriosis

Introduction. Endometriosis is a chronic inflammatory disease in which monocytes/macrophages play a key pathogenetic role. The peritoneal fluid (PF) cytokine profile can modulate recruited monocyte functions, determining their contribution to disease progression.Aim. To investigate stage-specific changes in the PF cytokine profile and their impact on functional reprogramming of monocytes in endometriosis.Methods. The study included 26 patients with endometriosis (stages I-III) and 6 controls. PF cytokine concentrations were measured by multiplex analysis (Bio-Plex). The effect of PF on MerTK, CCR2, PD-1, and PD-L1 expression by healthy donor monocytes was assessed by flow cytometry.Results. PF composition changed dynamically with disease stage: at stage I, RANTES and IL-6 increased; at stage II, IL-12 decreased and IL-1ra increased; at stage III, IFN-γ and IL-12 decreased. Stage I PF inhibited MerTK expression on monocytes, whereas stages II-III PF upregulated MerTK, PD-L1, PD-1, and CCR2. Pro-inflammatory cytokines negatively correlated with MerTK and PD-1 changes, while Th2 cytokines positively correlated with MerTK expression. Th2 cytokine levels were directly associated with serum CA-125 concentration.Conclusion. Stage-specific shifts in the PF cytokine profile initiate switching of monocytes from a pro-inflammatory to an immunosuppressive phenotype.