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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 NFκB and MAPK p38. We pinpointed megakaryocyte-derived NFκB2 transfer to human monocytes by mass spectrometry-based proteomics. Functionally, platelets proportionally restored impaired cytokine secretion in human monocytes lacking p38a and NFκB. We unveil the intercellular transfer of inflammatory regulators, positioning platelets as central checkpoints in monocyte-mediated inflammation.

Key Points

• Platelets are essential to TLR and NLR cytokine responses of human monocytes,

• Immune thrombocytopenia leads to monocyte immunoparalysis;

• Platelet supplementation reverses monocyte immunoparalysis;

• Platelets transfer NFκB that reactivates cytokine production in genetically deficient monocytes.