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

Abstract

ABSTRACTClassical CD14+monocytes are the predominant monocyte population in human blood. They are primarily engaged in host defense programs and secrete pro-inflammatory cytokines that orchestrate immune responses. While aberrant monocyte activity elicits cytokine storms, dysfunctional monocytes are associated with immunoparalysis, an equally life-threatening state of immunosuppression observed in severe sepsis, trauma, or respiratory viral infections. Hence, unraveling the mechanisms controlling monocyte functions is paramount in diverse clinical settings. Here, we reveal a critical dependency on platelets for the pro-inflammatory cytokine responses of human monocytes. We found that platelet removal from freshly isolated primary human monocytes causes monocyte immunoparalysis, characterized by transcriptional shut down of pro-inflammatory genes, and impaired cytokine secretion upon Toll-like and NOD-like receptor activation. Notably, anergic platelet-depleted monocytes can be reactivated upon their replenishment with autologous platelets. Moreover, monocytes from patients with immune thrombocytopenia display naturally impaired cytokine responses, which were also reversed by platelet supplementation. Mechanistically, we show that the platelet-monocyte crosstalk regulating monocyte cytokine responses is independent of classical co-stimulatory molecules, integrins, CCL5, CXCL12, Siglec-7, and Sialic Acids, and involves the trans-cellular propagation of platelet p38 MAPK signaling through platelet vesicles. Our findings delineate platelets as paramount regulators of monocyte innate immune functions.Key PointsPlatelets are essential to TLR and NLR cytokine responses of human monocytes,Platelet depletion causes a dynamic and reversible transcriptional reprogramming of human monocytes;Platelet supplementation reverts monocyte immunoparalysis in immune thrombocytopenia;Platelets are cellular sources of active transcription factors;Platelet supply p38 MAPK that reactivate cytokine responses in p38-inhibited monocytes.