Inflammatory Network of Liver Fibrosis and How It Can Be Targeted Therapeutically

Round 1

Reviewer 1 Report

"The manuscript " Inflammatory network of liver fibrosis and how it can be targeted therapeutically" by Lowe and colleagues is well written and comprehensive. It will be of interest in the liver fibrous field,

A table describing the therapeutic mode, and what is published or in clinical trial with references would be of great help.

Author Response

Authors would like to thank the reviewer for reading through our article and for the valuable comments.

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

This review deals with the cellular mechanisms involved in the liver fibrosis.

The manuscript is well written and organized.

There are some points that should be addressed.

1- The figure 2 is dealing with immune response in healthy liver as well as in the different stages of development of fibrosis. Actually, from this figure, it is not clear whether the immune response is different and why. The immune cells are not depicted, and it is not evident, if any. A different immune response could involve different effector and regulating cells (these cells are considered later on). It could be better to insert something in this figure to better introduce the topic.

Figure 3 is a representation of almost all cell potentially present in the liver (except for NK cells, these cells are not considered in this figure). There is no any evident representation of the events that can induce immune response, the antigen or stimuli involved and so on. This figure should be reorganized to show the cross-talk among the different lymphocyte subsets and their role in liver fibrosis. By itself, this figure as no relevance because it shows what a specific cell subsets can produce as cytokine, but this could be applied to any immune response.

Figure 5 with the classification of Tregs should be supported by references.

The Tregs appear to be a relevant subset involved, according to the authors, in the generation of fibrosis. Unfortunately, the review from the figure 5 to the page 23 is strictly focused on this cell subset, without showing any item to summarize the text content.

 In other words, It seems that the Treg are the key subset in inducing fibrosis, but no figure explains their role in the liver context.

Also, the therapy of fibrosis or causing agents of fibrosis is summarised in the figure 7 that is located at the end of the specific paragraph. This figure could be moved at the beginning to prepare the reader on the topic.

The considerations on CAR-T cells are of interest, but it is out of the topic of this review to show the generations of CAR-T cells. I would erase this figure. Instead, a better and detailed explanation with a cartoon of data reported on the use of CAR-T cells in liver fibrosis could be of help for the reader. 

Eventually, a table to show what described in the review is coming from experiments in animal model could be useful to see the state of the art on this topic.

English is good.

Author Response

Authors would like to thank the reviewer for reading through our article and for the valuable comments.

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The authors revised the review according to reviewer's queries.

The table inserted is of help, but actually it is too large and detailed. Please try to reduce and summarize better the message of each reference. 

English is good enough.

Author Response

We thank the reviewer for this comment. Authors have significantly reduced the size of Table 1.

Please see the attachment  

Author Response File: Author Response.pdf