Platelet-driven immunothrombotic remodeling programs convert ectopic endometrium into fibrotic, immune-privileged lesions

Fateme Aghajanzadeh Goodarzi, Goodarzi FA, Zahra Adib Majlesi, Majlesi ZA, Koutenaie A, Ailinasadolahpour Koutenaie, Faegheh Jomehpour, Jomehpour F, Abtahian A, Ameneh Abtahian, Asadi F, Fatemeh Asadi, Lordejani NA, Neda Ardeshiri Lordejani, Samira Azimi, Azimi S
International Immunopharmacology · 2026 · vol. 186 , pp. 117152 · doi:10.1016/j.intimp.2026.117152 · PMID:42470854 · W7169724658
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Activated platelets and fibrin within ectopic endometrial implants create an immunothrombotic niche that drives fibrotic remodeling and immune privilege by instructing stromal and immune cells via signaling molecules.

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Abstract

Endometriosis is a chronic, heterogenous disorder in which cyclical hemorrhage and repetitive repair generate ectopic implants that persist, recur, and drive pain and infertility; conventional frameworks emphasizing hormonal aberration and immune failure incompletely explain lesion fibrotic maturation and spatial heterogeneity. We synthesize human, experimental, and emerging spatial-omic evidence to advance a unifying mechanistic paradigm: cyclical bleeding seeds an immunothrombotic niche in which activated platelets and fibrin scaffolds organize immune cells and stromal responders, and platelet-derived signals, including P-selectin, TGF-β and platelet-derived microparticles (PMPs), act as upstream instructors of both immune dysregulation and fibrogenic stromal reprogramming. Quantitative histology and SHG imaging demonstrate spatial platelet hotspots that co-localize with NK suppression, CD163+ macrophage polarization and aligned collagen bundles in human lesions, while PMP proteomics and functional uptake assays link vesicular cargo to myofibroblast and reparative macrophage transcriptional programs. Mechanistically, platelet TGF-β and PMP cargo downregulate NK effector receptors (for example NKG2D), reprogram macrophages toward LOX-enriched matrix-remodeling states, and bias adaptive responses toward tolerance (Treg/Th17 imbalance), creating microdomains permissive for lesion survival. These processes engage a mechanobiological feedback loop: LOX-dependent collagen crosslinking increases stiffness, which amplifies myofibroblast and immune phenotypes and further recruits platelets, consolidating fibrotic architecture. We propose a research and translational roadmap, standardized PMP pipelines, integrated scRNA/spatial cohorts, ex vivo perturbations, and early proof-of-concept trials targeting adhesion (P-selectin), PMP biology, TGF-β activation or LOX, to test causality and enable precision interventions for the "immunofibrotic" endometriosis phenotype. Reframing endometriosis as a platelet-organized immunofibrotic disorder identifies novel druggable nodes and biomarker strategies with immediate potential to change both mechanistic research and clinical management.

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MeSH descriptors

Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets Blood Platelets

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