Platelets shape the immune response of primary human monocytes

Abstract

Monocytes are circulating immune cells essential to host defense, orchestrating immune responses through the secretion of immunomodulatory mediators. While exuberant monocyte-driven immune responses have life-threatening consequences, monocytic immune paralysis, characterized by abolished cytokine responses, compromises host defense and increases vulnerability to opportunistic infections. Hence, elucidating the mechanisms underlying monocyte-driven cytokine responses are relevant in clinical settings. In the circulation, monocytes are constantly surrounded by a large number of platelets. Beside their roles in hemostasis and coagulation, platelets can influence the function of leukocytes and steer immune responses. However, how platelets impact monocyte-driven immune responses is poorly understood. My findings uncover an unprecedented layer of platelet-induced regulation of monocyte immune function. Data presented in this thesis demonstrate the fundamental role of platelets in licensing the pro-inflammatory cytokine response of primary human monocytes. In contrast to previous assumptions, my data show that monocytes are not autonomous in their pro-inflammatory cytokine response, and require the interaction with platelets to reach their full pro-inflammatory capacity. Platelet depletion impairs the monocytic immune function through transcriptional shut-down of pro-inflammatory genes, alterations in kinase activities, and the subsequent disruption of pro-inflammatory cytokine secretion. Notably, this state of paralysis is reversed when platelet-depleted monocytes are reconstituted with autologous platelets. Interestingly, monocytes from patients with idiopathic thrombocytopenia display an impaired capacity to produce IL-1, IL-6β and TNFα. The addition of healthy platelets to monocytes from ITP patients ameliorates their cytokine responses. Mechanistically, I demonstrate that platelet depletion affects the NF-B κand p38 MAPK signaling pathways, identifying these as central components of the platelet-monocyte communication. Specifically, my data suggest that platelets license full monocyte cytokine responses via a two-step interaction: i) physical cell-cell contact and a subsequent ii) transfer of p38 or p38-downstream effectors via platelet-derived vesicles. Hence, the data in my thesis highlight platelets as a novel “ON” switch signal, facilitating the pro-inflammatory response of monocytes and maintaining them “ready and equipped” for an efficient host defense.