HIF-1α as a Central Regulator of Monocyte Responses to Hypoxia
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is a very well-written review. The authors have explained the relationship between acute hypoxia and monocytes thoroughly
The detailed insight into the crosstalk between HIF1-alpha and NF-kB is incredibly valuable. The description of Figure 5 explains the process very well. However, I suggest that the authors refine Figure 5 to improve its clarity. They can divide the figure into nucleus and cytoplasm and clearly define the movement of Nf-kb to the nucleus upon IκBα degradation in a hydroxylation-dependent manner.
I suggest that the authors add a figure on cytokine and chemokine induction in the HIF1 or hypoxia dependent manner. Cytokines and chemokines induction is a big part of the paper and a figure describing it would give a good overview for the readers. I understand it will not be possible to include everything described. In that case two figures defining the major processes discussed in the section would add up significantly.
If these changes are made, I believe this paper is a great contribution to the field.
Author Response
R) The detailed insight into the crosstalk between HIF1-alpha and NF-kB is incredibly valuable. The description of Figure 5 explains the process very well. However, I suggest that the authors refine Figure 5 to improve its clarity. They can divide the figure into nucleus and cytoplasm and clearly define the movement of Nf-kb to the nucleus upon IκBα degradation in a hydroxylation-dependent manner.
A) We thank the reviewer for the very positive and constructive comments, which helped us improve the clarity and impact of the manuscript.
As suggested, Figure 5 has been refined to enhance its clarity. The figure is now clearly divided into cytoplasmic and nuclear compartments, and the hydroxylation-dependent degradation of IκBα and subsequent translocation of NF-κB to the nucleus are explicitly illustrated.
R) I suggest that the authors add a figure on cytokine and chemokine induction in the HIF1 or hypoxia dependent manner. Cytokines and chemokines induction is a big part of the paper and a figure describing it would give a good overview for the readers. I understand it will not be possible to include everything described. In that case two figures defining the major processes discussed in the section would add up significantly.
If these changes are made, I believe this paper is a great contribution to the field.
A) As suggested, we have added a new figure summarizing cytokine and chemokine induction under hypoxic and HIF-1–dependent conditions (Figure 6). Given the central role of these mediators in the manuscript, this schematic provides an integrated overview of the major pathways discussed, while focusing on the most representative processes.
Overall, the inclusion of two schematic figures highlighting the key mechanisms discussed in this section significantly improves the accessibility and conceptual clarity of the review. We appreciate the reviewer’s assessment that, with these revisions, the manuscript represents a strong contribution to the field.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for Authors- Authors mainly discuss the HIF-1a involvement of monocyte in hypoxia environment, while the title and the abstract did not indicate clearly. Please modify the title and the abstract.
- Section "Conclusion" should make a further comprehensive integration of the above-mentioned signal pathways or crosstalks, further discuss their inner relationships under hypoxia environment. For instance, the sequence of these biological processes, the NF-KB signal pathway induces the cytokine and chemokines production, or the relationship between PKC activation and NF-KB.
Author Response
R) Authors mainly discuss the HIF-1a involvement of monocyte in hypoxia environment, while the title and the abstract did not indicate clearly. Please modify the title and the abstract.
A) We thank the Reviewer for this important comment. In response, we have revised both the title and the abstract to clearly reflect the main focus of the review on HIF-1α signaling in monocytes under hypoxic conditions. The new title, “HIF-1α as a Central Regulator of Monocyte Responses to Hypoxia”, explicitly highlights the central role of HIF-1α in monocyte biology in hypoxic environments. The abstract and the Simple Summary were revised accordingly to emphasize HIF-1α regulation, signaling crosstalk, and functional outcomes in monocytes and monocyte-derived macrophages.
R) Section "Conclusion" should make a further comprehensive integration of the above-mentioned signal pathways or crosstalks, further discuss their inner relationships under hypoxia environment. For instance, the sequence of these biological processes, the NF-KB signal pathway induces the cytokine and chemokines production, or the relationship between PKC activation and NF-KB.
A) We thank the Reviewer for this valuable suggestion. In response, we have revised the Conclusions section to better integrate the hypoxia-associated signaling pathways and their functional relationships. The revised text now explicitly describes the sequence of early hypoxic events, highlighting calcium-dependent PKC activation as an upstream signaling node linking hypoxia to NF-κB activation and HIF-1α regulation. We also clarify the role of NF-κB as an early driver of cytokine and chemokine production, as well as its bidirectional crosstalk with HIF-1α, reinforced by mitochondrial ROS signaling. These additions strengthen the mechanistic framework of the Conclusions and present acute hypoxia as a coordinated and temporally ordered signaling network. The Conclusions section has been updated accordingly.
We have also improved the English text.
Author Response File: Author Response.docx
