Platelet-derived transcription factors license human monocyte inflammation
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Abstract
CD14 + monocytes, the predominant population in human blood, are primarily engaged in host defense and pro-inflammatory cytokine responses. Aberrant monocyte activity causes life-threatening cytokine storms, while dysfunctional monocytes lead to ’immunoparalysis.’ Understanding the mechanisms controlling monocyte functions is therefore paramount. Here, we reveal platelets’ vital role in human monocytes’ pro-inflammatory responses. Low platelet counts in immune thrombocytopenia (ITP) patients, or platelet depletion in healthy monocytes result in monocyte immunoparalysis, characterized by reduced pro-inflammatory gene expression and weakened cytokine responses to immune challenge. Remarkably, adding fresh platelets reverses monocyte immunoparalysis. In mice, thrombocytopenia results in down-regulation of myeloid innate immune genes, and compromised host defense transcriptional programs in monocytes despite normal responses to LPS. Platelets control monocyte cytokines independently of traditional cross-talk pathways, acting as reservoirs of transcription factors like NFκB and MAPK p38. We pinpointed megakaryocyte-derived NFκB2 transfer to human monocytes by mass spectrometry-based proteomics. Functionally, platelets proportionally restored impaired cytokine secretion in human monocytes lacking p38a and NFκB. We unveil the intercellular transfer of inflammatory regulators, positioning platelets as central checkpoints in monocyte-mediated inflammation.
Key Points
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Platelets are essential to TLR and NLR cytokine responses of human monocytes,
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Immune thrombocytopenia leads to monocyte immunoparalysis;
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Platelet supplementation reverses monocyte immunoparalysis;
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Platelets transfer NFκB that reactivates cytokine production in genetically deficient monocytes.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/7024491.
Review of: Platelets supply p38 MAPK signaling that licenses pro-inflammatory
cytokine responses of human monocytes
BioRxiv. DOI: https://doi.org/10.1101/2022.08.10.503291
This preview was written by Chau Chiu Wang, a trainee in the Rio Sugimura lab at the University of Hong Kong as a part of his MBBS Enrichment Year Program.
Summary
Hawwari et al. investigated the role of platelet in the pro-inflammatory cytokine response of monocytes. They demonstrated that platelets supply p38 MAPK signal molecules to monocytes through direct contact. Depletion of platelets shut down pro-inflammatory genes while transfer platelets reactivated monocytes. This work provides insight into …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/7024491.
Review of: Platelets supply p38 MAPK signaling that licenses pro-inflammatory
cytokine responses of human monocytes
BioRxiv. DOI: https://doi.org/10.1101/2022.08.10.503291
This preview was written by Chau Chiu Wang, a trainee in the Rio Sugimura lab at the University of Hong Kong as a part of his MBBS Enrichment Year Program.
Summary
Hawwari et al. investigated the role of platelet in the pro-inflammatory cytokine response of monocytes. They demonstrated that platelets supply p38 MAPK signal molecules to monocytes through direct contact. Depletion of platelets shut down pro-inflammatory genes while transfer platelets reactivated monocytes. This work provides insight into immunoparalysis in thrombocytopenia patients and the novel role of platelets to activate the innate immune reaction.
The study revealed that platelets donate MAPK and transcription factors to monocytes. The successful activation of monocytes in the immunoparalysis state of ITP patients with platelet transfusion is clinically significant. This will reinforce the use of platelets as living-drug to target immune deficiency, autoimmunity, and cancers.
Major comments
Strengths:
The study has the following strengths
1. The novel mechanism of platelet-mediated inflammation. The study could also shed light on previous studies on platelets and their role in regulating innate immune reactions to supply detailed mechanisms.
2. In vivo murine model and human cell lines were used to validate the claim in an orthogonal way. The experiments were well designed and demonstrated that platelet depletion impaired cytokine secretion by monocyte and can be rescued by platelet supplements.
3. This study uses a wide range of technologies to confirm the findings including FACS, RNA seq, confocal imaging, immunoblotting, and kinase microarray in addition to an orthogonal approach to the hypothesis, increasing the validity of the study.
To be improved:
What could be a mechanism of platelets donating monocytes MAPK and transcription factors? Direct contact, but phagocytosis, was suggested. Recent studies support tunneling membrane nanotubes in the interaction between immune cells and stromal cells. Might be intriguing to check in platelet–monocyte interactions.
To further characterize the interaction of platelets with monocytes, I would suggest using calcium indicators for evidence of platelet degranulation or immunostaining of transcription factors.
Overall:
To summarize, the authors did a thorough study exploring the effect of a platelet on monocyte activation. Their work could contribute to the foundation of developing a treatment for inflammatory diseases like atherosclerosis and thrombo-inflammation in COVID-19 by using platelets as living drugs. Besides clinical implications, the study also adds new knowledge to platelet-mediated monocyte activation and may help to perfect in vitro monocyte models.
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