Monocytes secrete highly inflammatory cytokines that are critical for a proper immune response but can also lead to excessive inflammation when dysregulated. Similarly, dysfunctions in monocyte activity are associated with immunoparalysis, a state of hypo-responsiveness that halts the immune system’s ability to fend off invaders. How monocytes mediate these diverse functions remains a mystery. This study investigates the role of platelets in regulating monocyte inflammation, with a focus on human monocytes. We discovered that platelets are essential for the monocyte pro-inflammatory cytokine response. Platelet depletion in monocytes from healthy individuals and low blood platelet counts in patients with immune thrombocytopenia (ITP) caused monocyte immunoparalysis impairing their response to viral and bacterial ligands. Supplementation with fresh or healthy platelets reversed this condition and restored the monocyte‘s capacity to produce cytokines. Mechanistically, we found that pro-inflammatory signaling, including NF-κB and p38 MAPK, propagates from platelets to monocytes sustaining their inflammatory capacity. Platelet vesicles mediate this intercellular communication. These findings highlight a novel intercellular communication mechanism by which platelets regulate monocyte function. Clinically, this suggests potential therapeutic strategies involving platelet supplementation to counteract monocyte immunoparalysis in conditions such as ITP and other inflammatory diseases. Understanding the platelet-monocyte interaction may improve treatments for immune dysregulation and associated diseases.
