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

Ibrahim Hawwari, Nathalia Sofia Rosero Reyes, Lucas S. Ribeiro, Agnieszka Demczuk, Lino L Teichmann, Lisa Meffert, Damien Bertheloot, Bernardo S. Franklin
2022 bioRxiv   pre-print
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
more » ... ng 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 trans-cellular propagation of platelet p38 MAPK signaling through platelet vesicles licences the full cytokine responses of human monocytes. Our findings delineate platelets as paramount regulators of monocyte innate immune functions.HIGHLIGHTSPlatelets are essential to monocyte pro-inflammatory TLR and NLR responses.Platelet depletion causes a dynamic and reversible transcriptional reprogramming of human monocytes;Platelet supplementation reverts monocyte immunoparalysis in immune thrombocytopenia;Platelets supply p38 MAPK signalling that licenses full cytokine responses of human monocytes.
doi:10.1101/2022.08.10.503291 fatcat:daxiczkrfratvleqx5mca6rpou