NR4A Receptors in Immunity: Bridging Neuroendocrine and Inflammatory Pathways

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a very well-written review, a joy to read. It nicely summarizes our current knowledge on the NR4A nuclear receptors in immunity. A substantial amount of information on NR4As has already been reviewed in recent overview papers.

Comments:

1. At line 84: ”Nur response elements (NuRE; AAT(G/A)(C/T)CA) or DR5 elements[13, 14].” The sequence of NurRE is not correct, this is an ER6: TGATATTTnnnnnnAAATGCCA (Maira et al., 1999, doi: 10.1128/MCB.19.11.7549).
2. Line 134: “current research has significantly advanced our understanding of NR4A functions in macrophages and DCs [36].” Reference 36 is indeed a recent review but the original data on the role of NR4A function in macrophages and DCs is much older. It is better to rephrase this sentence.
3. Similarly as the previous comment; line 322, “Recent work by Moran et al.[61]”; this concerns a paper published in 2011.
4. Of the 98 references, 20 concern reviews on NR4As, of which 12 date from 2020 or are more recent (up to 2023). Ref #66 concerns an up to date review (2023) on NR4As in T cell function, and the role of the NR4A family in myeloid cells was last summarized in 2022 (ref #17). Since then, only 7 papers with novel original data (2023-2025) are mentioned of which only #44, 56, and 82 focus on NR4As in immunity. Altogether, this summing up illustrates that the current review, even though it is well-written, does not provide a tremendous amount of novel insight on NR4As in immunity.
5. Several paragraphs provide too much basic information on immune cells. For example, line 239-257, line 258-268, line 519-524, and line 559-575. These paragraph need to be more concise.

Minor comment:

Refs 17 and 36 are the same, ref 58 and 78 are the same.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

General comments:

The review article “NR4A Receptors in Immunity: Bridging Neuro-Endocrine and Inflammatory Pathways” by Ferreira and Santucci presents an informative overview of NR4A receptors in immune cells and immune-mediated diseases. However, it could be significantly strengthened by incorporating an expanded section outlining the specific roles NR4A receptors play at the intersection of neural, immune and endocrine signalling (response to stress hormone, NR4A-HPA-immune control of endocrine signals, systemic stress and metabolic states and their contribution to neuroinflammatory conditions). 

Streamlining the article's length (see below) and adding a focused section on neuro-immune-endocrine crosstalk would not only improve coherence with the review's title and abstract but would also provide the article with a distinctive and novel perspective. 

Specific comments:

1. Sections 1 and 2 would benefit from significant condensation-up to 50-60% as the key information could be presented and referenced more succinctly. The references are appropriate and can remain in place.
2. The clarity of Sections 3 and 4 would benefit from improved formatting as
 the bullet-point style is somewhat unclear and confusing for readers.
3. In Section 5, please verify the citation details for refences 87 and 88. It would also be helpful to review the wording in the third paragraph (lines 612-620) to improve for clarity, flow and precision.
4. Consider adding a Summary or Conclusion section outlining the review’s primary insights.
5. The Overview Table 1 could be improved with a summary, enhanced for readability to highlight key points & include references. Update to align with new section Neuro-immune-endocrine crosstalk section. Additionally, it would be beneficial to reference the table more frequently in the text.

Minor edits:
Line 110- remove “In”
Line 161-  edit “Tumoral”
Line 441- add to read “T-cell exhaustion”
Line 621- change “In another hand”
Lines 636-9- please develop the point made on “unique opportunity”, provide more detail & supporting information. 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This review provides a comprehensive overview of the roles of NR4A receptors in immunity, pathology, and metabolism, supported by a substantial number of references. However, the manuscript overall lacks a clear conceptual focus and often reads as a descriptive list of studies rather than a critical synthesis. Although the authors succeed in compiling a broad literature survey, the text does not sufficiently convey a unifying perspective or highlight novel insights.

 

Major Comments

1. Overly Descriptive Summaries

The manuscript frequently employs a “catalogue” style (e.g., “NR4A1 does X, NR4A3 does Y, NR4A2 is lowly expressed”) without addressing the broader implications of these differences. The significance of such contrasts is not sufficiently developed.

 

2. Weak Central Argument

While the review touches upon pathology, metabolism, and cancer, these discussions remain fragmented. A stronger integrative framework that connects these themes into a central message is needed.

 

3. Cumulative Rather than Integrative Structure

The sections on T cells, B cells, macrophages, NKT cells, pathology, and metabolism are presented sequentially, but transitions are weak. Each section could be more explicitly tied to an overarching question, e.g., “How do NR4A receptors function as context-dependent immune regulators?”

 

4. Lack of Precision in Key Sections

Line 212: The meaning of “pharmacological activation” is unclear and should be specified (e.g., ligand-based agonists? small molecules?).

Lines 621-629: The discussion on metabolic regulation requires stronger referencing with more specific and recent sources.

The section in lines 167-173 describes NR4A1’s role in macrophage metabolism but provides only vague statements without mechanistic detail, resulting in ambiguity rather than clarification.

 

5. Title-Content Mismatch

The title promises to “bridge neuro-endocrine and inflammatory pathways,” yet the manuscript contains very little discussion of neuro-endocrine mechanisms. Either the title should be revised or the missing content incorporated.

 

 

Minor Comments

1. Language and Clarity

Line 74: “48 members These receptors → 48 members. These receptors”

Line 110: “In During → During”

Line 163: “macrophages, These exception → macrophages. These exceptions”

Line 344: “receptor signaling[65] [6. → receptor signaling [65, 66]”

Line 391: “NR4A3[74] inking → NR4A3[74] linking”

Line 444: “it expression → its expression”

Line 505: “ssuppresses → suppresses”

Lines 446-447: The phrase “Increased IL-2 and IFNγ production, Reduced PD-1 expression and Improved T cell persistence”

 

2. Figure

Figure 1: “Lymphonode migration → Lymph node migration.”

 

 

Overall, this review has the potential to serve as a valuable reference. Still, in its current form, it falls short of the level of conceptual synthesis expected in a high-quality review article. Please try to revise the manuscript, focusing on:

- sharpening the central argument

- integrating findings into a coherent framework

- aligning the title with the actual content

- improving clarity, precision, and referencing.

Author Response

Please see the attachement

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

This is an interesting, timely, and comprehensive review on the roles of NR4A receptors in the immune system. The manuscript reads well overall and covers all the pertinent, recent literature on the topic. I only have the following (minor) comments:

1) Are there any clinically used pharmacotherapies reported to utilize these receptors for their effects? If so, please list them in a new Table or add them to the existing Table 1.

2) Please spell out all non-standard abbreviations used in the text, including those in Table 1 (DHA, CsnB, etc.).

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have no further suggestions

Reviewer 2 Report

Comments and Suggestions for Authors

The revisions and additions provided by the authors have strengthened the overall rigor and impact of the review.

For the final stage of editing, this reviewer recommends a thorough check of the reference list, including the citations in the table provided, to ensure full and appropriate alignment with all in-text citations. Examples include:

Line 73, refs 10,12,13

Line 517, refs 87, 88.

Also, within Section 5, can the following edits be applied:

1. Line 473, please replace ref 90 with one or both of the following references:

Helbling JC, Minni AM, Pallet V, Moisan MP. Stress and glucocorticoid regulation of NR4A genes in mice. J Neurosci Res. 2014 Jul;92(7):825-34. doi: 10.1002/jnr.23366. Epub 2014 Feb 19. PMID: 24753204.

Zhang D, Heaney AP. Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription. Cells. 2020 Apr;9(4):E900. DOI: 10.3390/cells9040900. PMID: 32272677; PMCID: PMC7226830.

2. Line 470, please include the following reference (below) and change text to read as outlined:

Murphy EP, Conneely OM. Neuroendocrine regulation of the hypothalamic pituitary adrenal axis by the nurr1/nur77 subfamily of nuclear receptors. Mol Endocrinol. 1997 Jan;11(1):39-47. doi: 10.1210/mend.11.1.9874. PMID: 8994186.

Their role in the stress response was further elucidated by the discovery of both NBRE and NurRE sequence binding motifs in the promoter of the POMC gene (the precursor for ACTH, α-MSH, and β-Endorphin)[15, 89, plus additional ref].

3. Line 475-476, please change the text to read:

This is demonstrated by NR4A1 binding to and activating functional NBRE and NurRE binding sites in the promoters of steroidogenic enzymes including P450c21[91].

 

 

 

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you for revising the manuscript.

Reviewer 4 Report

Comments and Suggestions for Authors

My comments have been addressed, nothing further.