Epigenetic and Metabolic Regulation of Macrophages during Gout

Round 1

Reviewer 1 Report

This is a  good review to provide update knowledge  upon  the activation mechanism of macrophages in gout.

but some drawbacks should be revised.

Major:  1.  "Abstract" should be enhanced to have our readers to catch up more key messages.

             2.  Figure legends should be more clear to help readers to understand the significance of this figure independently.

Minor :  Two articles  could be added for the  discussion of SOCS family and gout

1. Chen YH, Hsieh SC, Chen WY, Li KJ, Wu CH, Wu PC, Tsai CY, Yu CL. Spontaneous resolution of acute gouty arthritis is associated with rapid induction of the anti-inflammatory factors TGFβ1, IL-10 and soluble TNF receptors and the intracellular cytokine negative regulators CIS and SOCS3. Ann Rheum Dis. 2011 Sep;70(9):1655-63." could be added into references 

2. Orji OC, López-Domínguez MB, Sandoval-Plata G, Guetta-Baranes T, Valdes AM, Doherty M, Morgan K, Abhishek A. Upregulated expression of FFAR2 and SOC3 genes is associated with gout. Rheumatology (Oxford). 2023 Feb 1;62(2):977-983.

Good, but could be better.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

In this manuscript, the authors present their views on how immunometabolism may impact epigenetic modifications, transcription factor binding and other signaling processes that could lead to either excessive inflammation in response to MSU crystals or to adaptive stages leading to inflammation resolution in gout.

Major points

1.  This paper reads well and is interesting, however this reviewer feels more precision would be appreciated by the readership in describing what represents the opinion and hypothesis of the authors and what is significantly backed by the existing data. For example: section 3.1 histone lactylation data in response to MSUc is lacking; section 3.2 same for histone acetylation, the authors agree that „ the enhancer landscape induced by MSUc in macrophages remains unknown”; section 3.3 is titled „The histone landscape dictates transcription factor binding…etc” while no histone data related to the topic is reported. While this reviewer agrees that in general histones do dictate transcription factor binding, this framing could be very misleading.

2. I would suggest inserting a statement in the introduction briefly describing the overall viewpoints that will be presented in the review, making it clear that MSUc specific data related to all these processes are scarce but that many plausible and interesting research ideas can be envisioned under the framework of other studies and based on certain clear findings of some seminal studies on MSU. Each subsection should have a clearer separation between what is generally discussed about macrophage data and what has been shown to be fact in MSUc experiments.

3. I suggest reconsidering the title – there is really no data on clear epigenetic changes driven by MSUc that „dictate the activation mechanisms of macrophages” (other than the transcription factor enrichment analyses that are coming from transcriptome data). Of course, these are very likely correlated to differential chromatin accessibility but so far, we still need proof of this.

4.       Section 3.4 on lipidomics and implications for resolution of inflammation seems different from the rest of section 3. I suggest separating the proinflammatory reprogramming sections from the mechanisms that are framed as contributing more to resolution of inflammation.

5.       A discussion on what type of macrophages have been used in the MSUc studies that have been referenced would be very useful to the reader – human, mouse, primed/non primed, cell line/primary, differentiation protocols, etc. This is relevant in the context of MSU crystal literature showing limited effects of MSU in absence of second stimuli.

Minor points:

Section two is a general description of metabolomics techniques which I enjoyed reading but is not related to the topic of the paper, no connection is made between the various techniques, advantages or disadvantages described in the section and the findings of the key 5-6 references that report actual findings related to gout or hyperuricemia. The essential part of this section is lines 87-93 which briefly mention recent papers on plasma or serum metabolomics in gout or hyperuricemia, as opposed to the focus of the paper that looks at intracellular metabolic reprogramming in macrophages.

Line 106 „Some post-translational modifications of histones and epigenetic regulators impact 106 the inflammatory reaction during gout flares.” Please expand and provide reference.

Line 118 „Macrophages represent an elegant model for…” – this paragraph describes rather general epigenetic processes not restricted to macrophages.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

This review with focus on epigenetic and metabolic regulation in the activation of macrophages in gout is well written and gives a good overview on the current status of the field. The review is focussed on MSU crystals and their epigenetic mechanisms in gout. However, gout patients have MSU crystal depositions but also often hyperuricemia. Urate it self can initiate epigenetic modifications in myeloid cells. The authors should add a paragraph on the reported effects of soluble urate in gout patients and discuss the whether these epigenetic and metabolic changes are similar to MSU crystals or synergistic.

Author Response

Please see the attachment

Author Response File: Author Response.pdf