The Impact of the NLRP3 Pathway in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease
Round 1
Reviewer 1 Report
The review by Sheriff and Patricia details about the role of NLRP3 during NASH and ALD. The authors have elaborated the importance of the inflammosme on NASH and ALD nicely.
the review is well written and have covered major areas possible answers and gives a better understanding of the role of inflammosome in NASH and ALD.
However, the auhors should also comment on the impact of inflammosome on gut liver axis
Secondly, to describe the importance of inflammosome complex inhibitors as a few are already in clinical trials.
Author Response
We thank the reviewer for taking the time to read and appraise our review. We have addressed their comments (bold text) in plain text below.
"The review by Sheriff and Patricia details about the role of NLRP3 during NASH and ALD. The authors have elaborated the importance of the inflammosme on NASH and ALD nicely. The review is well written and have covered major areas possible answers and gives a better understanding of the role of inflammosome in NASH and ALD. However, the auhors should also comment on the impact of inflammosome on gut liver axis"
We are pleased that this reviewer considers the article well written, and agree that impact on the gut-liver axis is key to disease pathogenesis. We had considered the impact in our consideration of the role of intestinal microbiome/PAMPs, bile acid signalling and gut permeability in NAFLD/ALD in several places (eg section 2 110-119, section 3 155-162 and section 5 290-342 and in the treatment section 6 lines 354-358. ) However, in response to this comment we have added statements to highlight the interplay and cite new supporting references (70, 77 and 94).
"Secondly, to describe the importance of inflammosome complex inhibitors as a few are already in clinical trials."
Yes this is an important point – we did reference some inhibitors in section 6 but need to more explicitly refer to those in current clinical trial. Thus we have added new material and citations to the penultimate paragraph of section 6.
Reviewer 2 Report
This was a comprehensive review discussing the pathophysiology of NAFLD and ALD and the role of the NLRP3 inflammasome in driving liver injury. Although this is not novel, the addition of a review of potential therapies is a strength of the paper that adds to the growing body of literature focused on the inflammasome and liver disease.
An issue detracting from the readability of the paper was the poor grammar and multiple spelling issues found throughout, and particularly in section 2. The paper should be thoroughly edited.
Line 69 and elsewhere - oxidant should be replaced by oxygen.
Line 73 - DAMPs are not recognized by PAMPs. This should be corrected.
Lines 112-114 - FMT of microbes from lean individuals to obese individuals did not have lasting beneficial effects, which should be noted.
Lines 258-262 - It is unclear how MiR-223 in neutrophils suppresses activation of the inflammasome. The mechanism should be clarified. Is NLRP3 a target of MiR-223?
Figure 2 - the inflammasome complex is shown in the hepatocyte, however the figure caption and the text in the manuscript focus solely on the inflammasome in the macrophage. Therefore, discussion of the role of the inflammasome in hepatocytes should be included.
Author Response
We are greteful to the reviewer for their comments on our review (bold text) for which we have supplied specific responses below (plain text).
"This was a comprehensive review discussing the pathophysiology of NAFLD and ALD and the role of the NLRP3 inflammasome in driving liver injury. Although this is not novel, the addition of a review of potential therapies is a strength of the paper that adds to the growing body of literature focused on the inflammasome and liver disease.An issue detracting from the readability of the paper was the poor grammar and multiple spelling issues found throughout" "Line 69 and elsewhere - oxidant should be replaced by oxygen" We are pleased that the reviewer suggested our article was comprehensive and a valuable addition to the field. We aplogise for our typographical errors which have been corrected in the revised version of the manuscript. We have replaced 'oxidant' throughout.
"Line 73 - DAMPs are not recognized by PAMPs. This should be corrected. "Yes quite correct - we have amended as requested.
"Lines 112-114 - FMT of microbes from lean individuals to obese individuals did not have lasting beneficial effects, which should be noted" Agreed – have adjusted sentence to read “Similar transient effects linked to improvement in insulin sensitivity and repopulation of the gut with more beneficial species has been observed in obese humans treated with microbiota from lean individuals[25].”
"Lines 258-262 - It is unclear how MiR-223 in neutrophils suppresses activation of the inflammasome. The mechanism should be clarified. Is NLRP3 a target of MiR-223?". We apologize for the lack of clarity here – yes it has been suggested that miRNA 123 secreted as cargo in neutrophil extracellular vesciles silences the transcription of NLrP3 via interactions with the 3’-UTR. We have added detail to the corrected manuscript to explain this.
"Figure 2 - the inflammasome complex is shown in the hepatocyte, however the figure caption and the text in the manuscript focus solely on the inflammasome in the macrophage. Therefore, discussion of the role of the inflammasome in hepatocytes should be included." We have amended the figure legend to highlight the hepatocyte context and cite this and a new reference in the section of the manuscript where we cover inflammasome activation in hepatocytes (section 5 lines 333-345)
