Hawwari, Ibrahim: Platelets shape the immune response of primary human monocytes. - Bonn, 2023. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-69463
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-69463,
author = {{Ibrahim Hawwari}},
title = {Platelets shape the immune response of primary human monocytes},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2023,
month = jan,

note = {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.},
url = {https://hdl.handle.net/20.500.11811/10579}

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