P-Selectin and Platelet–Monocyte Interaction in Inflammation: Mechanisms, Hypothesis, and Open Questions

This review provides an integrated overview of how P-selectin-mediated platelet–monocyte interactions orchestrate key inflammatory processes in sterile and non-sterile pathological contexts. Inflammation presents a paradox: although it is a fundamental physiological process, uncontrolled activation can progress to a chronic state, contributing to the development of various inflammatory diseases. Platelets, previously considered to play a role exclusively in hemostasis, are now recognized as important immunomodulatory effectors capable of releasing inflammatory mediators and interact with leukocytes upon activation. The interaction between platelet P-selectin and monocyte PSGL-1 promotes the formation of platelet–monocyte aggregates, that together exert broad and profound inflammatory effects. These aggregates have been implicated in multiple pathological contexts, both sterile, such as atherosclerosis, obesity, autoimmune diseases, and hypertension, and non-sterile, such as sepsis and viral infections, highlighting their role as a common axis of immune and inflammatory regulation. This review integrates shared but contextualized mechanistic pathways and outlines current hypotheses regarding how platelet–monocyte interactions may operate in sterile and pathogen-induced inflammation. We further discuss emerging evidence connecting P-selectin signaling to metabolic reprogramming, vascular dysfunction, and immunothrombosis, as well as its possible influence on monocyte activation and phenotype in diverse inflammatory settings, discussing open questions, perspectives, and challenges in the field. By integrating interdisciplinary findings, this review highlights P-selectin-dependent platelet–leukocyte interactions as central axis in inflammation and promising therapeutic targets.