Platelets supply p38 MAPK signaling that licenses pro-inflammatory cytokine responses of human monocytes

Abstract

CD14+ monocytes, the predominant population in human blood, are primarily engaged in host defense and pro-inflammatory cytokine responses. Aberrant monocyte activity causes life-threatening cytokine storms, while dysfunctional monocytes lead to immunoparalysis. Understanding the mechanisms controlling monocyte functions is therefore paramount. Here, we reveal platelets vital role in human monocytes pro-inflammatory responses. Low platelet counts in immune thrombocytopenia (ITP) patients, or platelet depletion in healthy monocytes result in monocyte immunoparalysis, characterized by reduced pro-inflammatory gene expression and weakened cytokine responses to immune challenge. Remarkably, adding fresh platelets reverses monocyte immunoparalysis. In mice, thrombocytopenia results in down-regulation of myeloid innate immune genes, and compromised host defense transcriptional programs in monocytes despite normal responses to LPS. Platelets control monocyte cytokines independently of traditional cross-talk pathways, acting as reservoirs of transcription factors like NF{kappa}B and MAPK p38. We pinpointed megakaryocyte-derived NF{kappa}B2 transfer to human monocytes by mass spectrometry-based proteomics. Functionally, platelets proportionally restored impaired cytokine secretion in human monocytes lacking p38a and NF{kappa}B. We unveil the intercellular transfer of inflammatory regulators, positioning platelets as central checkpoints in monocyte-mediated inflammation. Key PointsO_LIPlatelets are essential to TLR and NLR cytokine responses of human monocytes, C_LIO_LIImmune thrombocytopenia leads to monocyte immunoparalysis; C_LIO_LIPlatelet supplementation reverses monocyte immunoparalysis; C_LIO_LIPlatelets transfer NF{kappa}B that reactivates cytokine production in genetically deficient monocytes. C_LI