Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes
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Abstract
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.
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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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