TY  - JOUR
AU  - Hawwari, Ibrahim
AU  - Rossnagel, Lukas
AU  - Rosero, Nathalia
AU  - Maasewerd, Salie
AU  - Vasconcelos, Matilde B
AU  - Jentzsch, Marius
AU  - Demczuk, Agnieszka
AU  - Teichmann, Lino L
AU  - Meffert, Lisa
AU  - Bertheloot, Damien
AU  - Secchim Ribeiro, Lucas
AU  - Kallabis, Sebastian
AU  - Meissner, Felix
AU  - Arditi, Moshe
AU  - Atici, Asli E
AU  - Noval Rivas, Magali
AU  - Franklin, Bernardo S
TI  - Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes
JO  - EMBO molecular medicine
VL  - 16
IS  - 8
SN  - 1757-4676
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2026-00088
SP  - 1901 - 1929
PY  - 2024
AB  - In humans, blood Classical CD14+ monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with 'immunoparalysis', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets' vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.
KW  - Humans
KW  - Monocytes: metabolism
KW  - Monocytes: immunology
KW  - Blood Platelets: metabolism
KW  - Blood Platelets: immunology
KW  - Cytokines: metabolism
KW  - Transcription Factors: metabolism
KW  - Transcription Factors: genetics
KW  - Inflammation: metabolism
KW  - Hyperinflammation (Other)
KW  - Immune Thrombocytopenia (Other)
KW  - Immunoparalysis (Other)
KW  - Inflammasomes (Other)
KW  - Toll-like Receptors (Other)
KW  - Cytokines (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1038/s44321-024-00093-3
UR  - https://pub.dzne.de/record/284080
ER  -