Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled “Interleukin-17A (IL-17A): Molecular Characteristics and Its Physiological and Pathological Significance - From Molecular Structure to Clinical Applications” presents an outlook on the molecular characteristics of the IL-17–IL-17R signaling and on the pleiotropic effects of this pathway, which is potentially involved in the pathogenesis of several autoimmune, neurodegenerative, and psychiatric disorders.

 The neuroimmune role of the IL-17 pathway represents a hot topic in biomedical research, with several studies that have been published on this theme during recent years. The proposed review provides a concise overview of the IL-17-centered axis but does not comprehensively cover the existing literature and has some major limitations:

 - The potential role played by IL-17 in modulating synaptic function is not adequately addressed, which may constitute an IL-17-dependent pathogenic mechanism distinct from its well-established involvement in regulating neuroinflammation during various neuroinflammatory and neurodegenerative diseases (such as multiple sclerosis and Alzheimer’s disease). Moreover, it is not clearly stated that the IL-17 receptor is also expressed by neuronal cells, both in cortical and subcortical regions; an issue that is highly relevant to the discussion of the functional roles of the IL-17 axis. Moving from these considerations, I would suggest to expand the section “Functional Implications of IL-17 Signaling in the CNS”, also discussing other recent studies on the theme (see for example: Ribeiro M, et al, Sci Immunol. 2019, doi: 10.1126/sciimmunol.aay5199; Di Filippo M, et al. Cell Rep. 2021, doi: 10.1016/j.celrep.2021.110094; Brigas HC et al., Cell Rep. 2021,  doi: 10.1016/j.celrep.2021.109574).

 - The section on IL-17A-targeted therapies briefly describes some reports, but could benefit from a balanced discussion of adverse effects and unmet challenges in clinical translation, especially regarding CNS penetration and safety.

 - In the section “The Cellular Heterogeneity Underlying IL-17A Production”, the Authors should also mention IL-17-producing microglial cells as key actors in the IL-17-centered neuroimmune axis in the CNS (as described in some papers mentioned before).

 Minor:

- Page 3, line 100-106: repeated ILC3 description.

Author Response

Responses to Reviewer #1

 

Comment:

 

“The manuscript does not sufficiently discuss the neuronal expression of IL-17 receptors and the potential role of IL-17 in modulating synaptic function. The section ‘Functional Implications of IL-17 Signaling in the CNS’ should be expanded to incorporate recent findings (Ribeiro 2019, Di Filippo 2021, Brigas 2021).”

 

Response:

 

We thank the reviewer for this valuable comment. We have substantially expanded the CNS-related portion of the manuscript. In the revised section “Functional Implications of IL-17 Signaling in the CNS”, we now explicitly describe:

 

the expression of IL-17RA and IL-17RC not only in glial cells but also in neurons,

the potential of IL-17A to directly modulate synaptic function and neuronal plasticity, and experimental evidence demonstrating IL-17A’s influence on neuronal activity and behavior.

 

To support these statements, we have added the recommended references:

 

Ribeiro et al., Sci Immunol. 2019,

Di Filippo et al., Cell Reports 2021,

Brigas et al., Cell Reports 2021.

 

These references now appear in the CNS section of the revised manuscript (page 05, lines 194–196).

 

Comment 2

 

“The discussion of IL-17A-targeted therapies should be more balanced, addressing adverse effects and challenges related to CNS targeting.”

 

Response:

 

We agree with the reviewer that a more balanced evaluation of IL-17A-targeted therapies is needed.

Therefore, in the section “Pathophysiological Insights and Therapeutic Target Potential of IL-17A”, we added a new subsection titled:

 

“Therapeutic Implications of IL-17A/IL-17 Receptor Blockade.”

 

In this subsection, we now include:

 

a concise summary of the clinical efficacy of IL-17A-targeting biologics (secukinumab, ixekizumab) and IL-17RA-targeting brodalumab, safety considerations such as mucocutaneous Candida infections, the potential exacerbation of inflammatory bowel disease, and challenges specifically related to CNS diseases (e.g., blood–brain barrier permeability, limited clinical evidence).

 

These additions provide a more comprehensive and balanced discussion, as requested.

 

 

Comment 3

 

“In the section “The Cellular Heterogeneity Underlying IL-17A Production”, the Authors should also mention IL-17-producing microglial cells as key actors in the IL-17-centered neuroimmune axis in the CNS (as described in some papers mentioned before)”

 

Response:

 

We appreciate the reviewer’s helpful suggestion. In the revised manuscript, we have incorporated a clear description of IL-17-producing microglia as essential contributors to IL-17A-mediated neuroimmune regulation within the CNS.

 

Specifically, in the section “Functional Implications of IL-17 Signaling in the CNS”, we now state that IL-17A is produced not only by infiltrating Th17 cells but also by resident microglia, astrocytes, and subsets of neurons. We also emphasize that microglia express IL-17 receptors, enabling them to both produce and respond to IL-17A, thereby amplifying local neuroinflammatory responses.

 

These additions directly address the reviewer’s comment and better reflect the current understanding of the IL-17-centered neuroimmune axis.

 

Minor Comment

“- Page 3, line 100-106: repeated ILC3 description.”

 

We thank the reviewer for pointing out the duplicated description of ILC3s. In the revised manuscript, we have removed the repeated sentence and retained a single, streamlined description of ILC3s in the section “The Cellular Heterogeneity Underlying IL-17A Production.” This correction eliminates redundancy and improves the text's clarity.

 

Final Statement

 

We appreciate the reviewer’s constructive feedback, which significantly improved the clarity, accuracy, and scientific rigor of our manuscript. All requested corrections and additions have now been fully incorporated into the revised version.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Sanaka et al describe the basics of IL17 family biology highlight connections to CNS.

While the text of the review read well, some significant aspects of IL17 biology do not have sufficient citations – namely the key role for IL17A & IL17F in psoriasis, psoriatic arthritis, hidradenitis suppurativa, giant cell arteritis etc. This is particularly needed here since the approved anti-IL17 therapeutics have been shown to act on those diseases and provide relief for many patients.  For example, lines 44-52 about autoimmune disease & IL17A-targeted therapeutics need some example references to be of value to the reader.

Other comments:

• Lines 174-177: References needed for IBD, RA conenctions
• Ref 27 suggest IL17 known to modulate neuronal plasticity and synaptogenesis – but IL17 is not mentioned in this reference. Please correct.
• Lines 196-199: need reference for IL17A in ischemic brain injury

Ref 25 is listed incompletely and cannot be used as such – may be a truncated typo

Author Response

Responses to Reviewer #2

 

We thank the reviewer for the careful evaluation of our manuscript and for the constructive comments.

We have thoroughly revised the manuscript in accordance with all suggestions.

Our detailed responses are provided below.

 

Comment 1

 

“Some significant aspects of IL-17 biology do not have sufficient citations – namely the key role of IL-17A & IL-17F in psoriasis, psoriatic arthritis, hidradenitis suppurativa, giant cell arteritis etc. Lines 44–52 need references.”

 

Response:

 

We agree that additional citations were necessary better to support the IL-17A–related pathophysiology in autoimmune diseases. To address this, we strengthened the psoriasis-related immunopathology by adding a new subsection titled:

 

“Psoriasis as a Prototypical IL-17A–Driven Autoimmune Disease.”

This subsection explains the central role of IL-17A and IL-17F in keratinocyte activation and psoriatic inflammation, and is now supported by the following new references:

 

Lowes et al., 2014

Gaffen et al., 2014

Blauvelt & Chiricozzi, 2018

Johansen et al., 2009

 

These citations now appear in the revised manuscript (page 04, lines 181–188).

This revision directly addresses the reviewer’s request for stronger and clearer referencing.

 

Comment 2

 

“Lines 174–177: References needed for IBD and RA connections.”

 

Response:

 

We thank the reviewer for pointing this out. In the revised manuscript, we added authoritative references supporting the association of IL-17A with inflammatory bowel disease and rheumatoid arthritis.

These include:

 

Kuwabara et al., 2017 (Mediators Inflamm)

McGeachy et al., 2019 (Immunity)

 

The revised references now substantiate the discussion in this section (Page 4, Lines 174–177).

 

Comment 3

 

“Ref 27 suggests IL-17 modulates neuronal plasticity and synaptogenesis – but IL-17 is not mentioned in this reference. Please correct.”

 

Response:

 

We fully agree. We corrected this error by removing the inappropriate use of reference 27 in the context of neuronal plasticity. Instead, we now cite appropriate IL-17–related CNS references, including:

 

Ribeiro et al., Sci Immunol 2019

Di Filippo et al., Cell Reports 2021

Brigas et al., Cell Reports 2021

 

These references appropriately support IL-17A’s potential influence on neuronal function (see revised lines around IL-17A CNS section). Furthermore, the CNS section has been updated to reflect current evidence on IL-17A’s effects on neuronal function, incorporating more suitable literature as recommended by the reviewers. This ensures that accurate and up-to-date references now support all statements regarding IL-17A’s relevance to neuronal biology.

 

 

Comment 4

 

“Lines 196–199: need reference for IL-17A in ischemic brain injury.”

 

Response:

 

We thank the reviewer for this critical comment.

In the revised manuscript, we added appropriate references to support the statements regarding IL-17A's role in ischemic brain injury. Specifically, we now cite Kuwabara et al. (2017, Mediators of Inflammation), which provides comprehensive evidence that IL-17A contributes to ischemic brain pathology by:

 

amplifying acute inflammatory responses,

promoting neuronal injury and cell death,

increasing blood–brain barrier permeability, and

activating microglia and astrocytes.

 

These citations have been added to the end of the relevant paragraph (page 5, lines 208–209 in the revised manuscript), thereby substantiating the discussion with appropriate experimental and mechanistic evidence.

 

Comment 5

 

“Ref 25 is listed incompletely and cannot be used – may be a truncated typo.”

 

Response:

 

We thank the reviewer for identifying this. Reference 25 was indeed incomplete in the original version.

We corrected this by replacing the incomplete citation with a complete and accurate reference entry, following the journal’s formatting guidelines. The reference list has been thoroughly checked to ensure no other truncated entries remain.

 

Final Statement

 

We appreciate the reviewer’s constructive feedback, which significantly improved the clarity, accuracy, and scientific rigor of our manuscript. All requested corrections and additions have now been fully incorporated into the revised version.

Reviewer 3 Report

Comments and Suggestions for Authors

Interleukin-17 (IL-17) is a pro-inflammatory cytokine involved in chronic inflammation occurring in allergies and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis.

IL-17 plays an important role, especially in the pathogenesis of psoriasis. Psoriasis is a chronic, immune-mediated disease.  The interleukin 17 pathway has been identified as a critical axis in its pathogenesis. 

In this review, the authors should highlight the important role of IL-17 in the pathogenesis of autoimmune diseases, especially psoriasis.

 

Critical evaluation of the monoclonal antibodies  targeting IL-17A and IL-17 receptors (e.g., Ixekizumab, Secukinumab, and Brodalumab) in various immune-mediated diseases should  be presented.

Author Response

Responses to Reviewer #3

 

Interleukin-17 (IL-17) is a pro-inflammatory cytokine involved in chronic inflammation occurring in allergies and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis.

 

We thank the reviewer for the thoughtful and constructive comments. We appreciate the reviewer’s valuable comments, which have greatly improved the clarity and scientific depth of the manuscript. All requested modifications have been incorporated into the revised version. Below, we describe how we have revised the manuscript in direct response to the reviewer’s suggestions.

 

Comment 1:

 

“Psoriasis represents a major IL-17–driven autoimmune disease and the manuscript should emphasize the central pathogenic role of IL-17A in psoriasis.”

 

Response:

 

We fully agree with the reviewer’s comment. To address this point, we added a new dedicated subsection entitled “Psoriasis as a Prototypical IL-17A–Driven Autoimmune Disease” in the revised manuscript (see page 04, line 181– page 05, Line 188).

 

In this subsection, we elaborated on:

 

the indispensable role of IL-17A in driving psoriatic inflammation,

the synergistic actions of IL-17A and IL-17F on keratinocyte activation,

the establishment of a self-amplifying inflammatory loop in psoriatic skin, and

the dysregulation of the IL-23/IL-17 axis as a defining immunological hallmark of psoriasis.

 

These additions now appear in the revised text as follows:

 

“IL-17A plays a central and indispensable role in the pathogenesis of psoriasis… (subsection beginning after the Evolutionary Conservation section).”

 

This revision directly addresses the reviewer’s request to strengthen the psoriasis-related immunopathology section.

 

Comment 2:

 

“A more explicit and critical evaluation of IL-17A/IL-17RA-targeted monoclonal antibodies—such as ixekizumab, secukinumab, and brodalumab—should be included.”

 

Response:

 

We appreciate this critical suggestion. To respond, we substantially revised the section

“Pathophysiological Insights and Therapeutic Target Potential of IL-17A.” Immediately after the description of IL-17A-targeted therapies (original lines around 317–324), we inserted a new subsection titled:

 

“Therapeutic Implications of IL-17A/IL-17 Receptor Blockade”（page 06, lines 242–255）

 

This subsection now includes:

 

a clear description of the clinical efficacy of secukinumab, ixekizumab, and brodalumab in psoriasis and psoriatic arthritis, improvement in disease severity and skin clearance, patient quality-of-life benefits, and a balanced evaluation of safety, including increased risk of Candida infections, potential exacerbation of inflammatory bowel disease.

 

These revisions appear in the manuscript as:

 

“Therapeutic monoclonal antibodies targeting IL-17A or the IL-17 receptor, including secukinumab, ixekizumab, and brodalumab (39–41), have demonstrated remarkable clinical efficacy… However, IL-17 blockade is associated with an increased risk of mucocutaneous Candida infections (42) and may exacerbate inflammatory bowel disease (43)… ”

 

This new section provides the clinical context and critical assessment requested by the reviewer.

 

Comment 3:

 

“More discussion on therapeutic relevance should be included in the context of immune-mediated diseases.”

 

Response:

 

By adding the two subsections described above—one on psoriasis pathogenesis and one on IL-17A/IL-17RA–targeted biologics—we have significantly expanded the therapeutic relevance of IL-17A biology across immune-mediated diseases. These revisions clarify both the mechanistic and clinical significance of IL-17A, fully addressing the reviewer’s request.

 

Reviewer 4 Report

Comments and Suggestions for Authors

The authors have presented a manuscript titled: "Interleukin-17A (IL17-A): Molecular Characteristics and Its Physiological and Pathological Significance – From Molecular Structure to Clinical Application."

The topic is highly relevant, given the significant attention currently focused on IL-17A in various inflammatory pathologies, such as psoriasis. However, there are several points that require revision:

• Focus and Title: It remains unclear whether the primary focus of this review is to describe the role of IL-17A specifically within the Central Nervous System (CNS). If this is the case, the authors should update the title accordingly and expand this section significantly to improve clarity.
• Terminology: I would recommend not classifying psoriasis strictly as an autoimmune disease, but rather as an immune-mediated disease.
• Structure and Subheadings: The current manuscript contains an excessive number of subheadings, which creates confusion. I suggest restructuring the sections as follows:
• Interleukin-17A: including all related sub-sections (Molecular structure and regulation, transcriptional regulation, expressing cells, etc.).
• The IL-17A Receptor: including related sub-sections (Mechanisms and functions, expressing cells, and signaling pathways).
• Evolution and Conservation of Signaling.
• Pathologies Associated with IL-17A Pathway Dysregulation: with sub-sections (e.g., Psoriasis).
• Implications of IL-17 Signaling in the Central Nervous System: (linking to psychiatric disorders).
• Therapies.
• Conclusions.
• It would be appropriate to include figures to improve the flow of the review and make it more engaging for the reader.
• Certain topics should be explored in greater depth, depending on the intended scope of the review (as mentioned above). For instance, there is recent literature regarding the role of IL-17 in keratinocyte populations that should be considered (e.g., Palazzo et al., 2025).
• A formal reference to Figure 1 is missing within the main text.
• Please review the references throughout the manuscript. Several sections lack proper citations (e.g., lines 143–156).

Author Response

Responses to Reviewer 4

Manuscript ID: receptors-3861224

Revised Title: Interleukin-17A (IL-17A): Molecular Mechanisms and Its Roles in Immune and Neuroimmune Systems

Authors: Sae Sanaka, Asumi Kubo, Sara Kamiya, Kenyu Nakamura, Tetsuya Sasaki*

Dear Reviewer 4,

We are deeply grateful for your thorough and insightful review of our manuscript. Your comments have been extraordinarily constructive and have fundamentally reshaped both the scope and the presentation of this review. In response to your feedback, we have: updated the title to reflect the integrative immune/neuroimmune focus, restructured the entire manuscript according to your proposed framework, expanded the body text from approximately 2,800 to 4,900 words, added two new figures (bringing the total from one to three), integrated recent literature you specifically recommended (Palazzo et al., 2025), and conducted a comprehensive citation audit across all sections.

Below, we provide a detailed, point-by-point response to each of your seven specific comments. For each comment, we quote your original remark, explain how we have addressed it, and—where applicable—cite the specific sections of the revised manuscript where the corresponding changes can be seen. A companion highlighted manuscript (manuscript_highlighted_v7.docx) shows all content modifications and additions in red for direct visualization.

Comment 1 — Focus and Title

Reviewer 4 Comment: It remains unclear whether the primary focus of this review is to describe the role of IL-17A specifically within the Central Nervous System (CNS). If this is the case, the authors should update the title accordingly and expand this section significantly to improve clarity.

Authors' Response: We thank the Reviewer for this important clarifying question, which prompted us to reconsider the scope and framing of the review at a fundamental level. Upon careful reflection, we acknowledge that the original title ("Molecular Characteristics and Its Physiological and Pathological Significance — From Molecular Structure to Clinical Applications") was indeed ambiguous and did not adequately communicate the integrative focus on both immune and neuroimmune systems that is central to our review.

We have accordingly revised the title to:

"Interleukin-17A (IL-17A): Molecular Mechanisms and Its Roles in Immune and Neuroimmune Systems"

This new title accurately reflects our intent: to cover the complete biology of IL-17A from its molecular mechanisms through its classical immunological functions to its emerging and distinctive roles in the central nervous system. The phrase "Immune and Neuroimmune Systems" captures both the CNS-specific actions of IL-17 (in microglia, astrocytes, oligodendrocytes, and neurons) and the peripheral–central immune crosstalk exemplified by maternal immune activation and neurodegenerative disease.

In parallel with the title revision, we have substantially expanded the CNS section from a single combined section in the original manuscript to five distinct subsections in the revised version:

6.1. Physiological Roles in the Healthy Brain

6.2. Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

6.3. Alzheimer's Disease and Neurodegeneration (new)

6.4. Ischemic Brain Injury

6.5. Psychiatric Disorders and Autism Spectrum Disorder

Each subsection has been expanded with mechanistic detail and supported with appropriate primary literature. Section 6.1 now discusses IL-17 receptor diversity across astrocytes, microglia, oligodendrocytes, and neurons, and incorporates the recent brain-wide mapping study by Lee et al. (2025) [Ref. 29] on IL-17E/IL-17RB neuromodulation. To further clarify the neuroimmune focus visually, a new Figure 3 has been added to illustrate the proposed mechanism of IL-17A in ASD pathogenesis, integrating maternal immune activation, gut microbiota, placental transmission, receptor signaling, and fetal neurodevelopmental consequences.

[Change in manuscript — Title, Section 6 (pp. 9–13), new Section 6.3, new Figure 3]: Title revised; CNS section reorganized into 6.1–6.5; new subsection 6.3 (Alzheimer's Disease and Neurodegeneration) added; new Figure 3 added with explicit text reference in Section 6.5.

Comment 2 — Terminology

Reviewer 4 Comment: I would recommend not classifying psoriasis strictly as an autoimmune disease, but rather as an immune-mediated disease.

Authors' Response: We fully agree with the Reviewer, and we appreciate this important terminological correction. Psoriasis is indeed more accurately characterized as an immune-mediated inflammatory disease rather than a classical autoimmune disease, given the lack of well-defined autoantigens and the central role of dysregulated innate and adaptive immunity in its pathogenesis. Classification as "immune-mediated" is now the preferred terminology in the contemporary dermatological and immunological literature.

We have revised every occurrence of "autoimmune" in the context of psoriasis throughout the manuscript to "immune-mediated." This change appears in the abstract, introduction (paragraph 2), evolutionary conservation section (Section 4), and therapies section (Section 7). Conditions for which "autoimmune" remains the standard and accurate term (e.g., experimental autoimmune encephalomyelitis, which is its established name) have been retained unchanged.

[Change in manuscript — Abstract, Section 1, Section 4, Section 7.1, Section 7.4]: All psoriasis-related instances of "autoimmune" replaced with "immune-mediated"; EAE retained with "autoimmune" because it is the established disease name.

Comment 3 — Structure and Subheadings

Reviewer 4 Comment: The current manuscript contains an excessive number of subheadings, which creates confusion. I suggest restructuring the sections as follows: Interleukin-17A (including all related sub-sections); The IL-17A Receptor (including related sub-sections); Evolution and Conservation of Signaling; Pathologies Associated with IL-17A Pathway Dysregulation (with sub-sections, e.g., Psoriasis); Implications of IL-17 Signaling in the Central Nervous System (linking to psychiatric disorders); Therapies; Conclusions.

Authors' Response: We are very grateful for this excellent structural recommendation, which substantially improved the clarity and navigability of the review. We have completely reorganized the manuscript according exactly to your proposed framework. The revised manuscript now follows the hierarchical structure below:

1. Introduction
2. Interleukin-17A — 2.1 The IL-17 Family; 2.2 Molecular Structure; 2.3 Transcriptional Regulation; 2.4 Cellular Sources
3. The IL-17A Receptor — 3.1 Receptor Family and Structural Features; 3.2 Cellular Heterogeneity of Expression; 3.3 Signaling Pathway; 3.4 Negative Regulation
4. Evolutionary Conservation of IL-17 and Its Signaling Pathways
5. Pathologies Associated with IL-17A Pathway Dysregulation — 5.1 Psoriasis; 5.2 Rheumatoid Arthritis; 5.3 Inflammatory Bowel Disease; 5.4 Ankylosing Spondylitis
6. Implications of IL-17 Signaling in the Central Nervous System — 6.1–6.5 as detailed in response to Comment 1
7. Therapies — 7.1 Approved Biologics; 7.2 Safety Considerations; 7.3 Emerging Strategies; 7.4 CNS Applications
8. Conclusions and Future Prospects

This reorganization consolidates the previously fragmented subheadings of the original manuscript (approximately 13 top-level sections) into 8 clearly defined sections with 21 logically organized subsections, matching the framework you proposed. Readers can now navigate the review intuitively from molecule → receptor → conservation → peripheral pathology → CNS implications → therapies → conclusions.

[Change in manuscript — Entire manuscript]: Full structural reorganization; all subheadings consolidated into 8 sections following the Reviewer's exact proposed framework.

Comment 4 — Figures

Reviewer 4 Comment: It would be appropriate to include figures to improve the flow of the review and make it more engaging for the reader.

Authors' Response: We fully agree. To improve the visual flow and reader engagement, we have added two new figures, bringing the total from one to three. Each figure is explicitly referenced in the main text at its corresponding section and is accompanied by a detailed, self-contained caption. The three figures collectively cover the molecular, cellular, and disease-related dimensions of IL-17A biology:

Figure 1 (retained; explicitly referenced in new Section 3.3): Molecular architecture of the IL-17 family and IL-17 receptors. Illustrates ligand–receptor pairing across the entire IL-17 family, FnIII extracellular domains, SEFIR intracellular domains, and the Act1–TRAF6–TAK1 adaptor cascade that activates NF-κB, MAPK, and C/EBP transcription programs. This figure provides the molecular foundation for Section 3 (The IL-17A Receptor).

Figure 2 (new; explicitly referenced at the end of Section 2.4): Differentiation of CD4⁺ helper T cell lineages and their effector functions. Situates Th17 cells within the broader landscape of helper T cell subsets (Th1, Th2, Th17, TFH, Treg) with their master transcription factors (T-bet, GATA-3, RORγt, Bcl-6, Foxp3) and characteristic cytokine profiles. The Th17 arm (IL-6/TGF-β → RORγt → IL-17A) is highlighted, directly supporting Sections 2.3 and 2.4. Adapted from Ivanov et al., 2006 (Ref. 9, already cited in the manuscript).

Figure 3 (new; explicitly referenced at the end of Section 6.5): Proposed mechanism of IL-17A in the pathogenesis of autism spectrum disorder (ASD). Integrates maternal immune activation (MIA), gut microbiota dysbiosis including segmented filamentous bacteria, placental barrier transmission, IL-17 receptor signaling in fetal cells (Act1–TRAF6/TRAF3–TAK1 → NF-κB/MAPK/C/EBP), and fetal neurodevelopmental consequences (microglial dysfunction, cortical dysplasia, neural stem cell effects, BBB abnormalities). This figure is directly aligned with the integrative immune/neuroimmune focus reflected in the new title. Adapted from Kubo et al., Neuroglia 2025 (Ref. 30), published under CC BY open access.

[Change in manuscript — New Figures 2 and 3 inserted after Figure 1; explicit text references added to Sections 2.4, 3.3, and 6.5]: Two new figures added (total 1 → 3); all three figures now explicitly referenced in the main text; captions expanded and self-contained.

Comment 5 — Depth of Specific Topics

Reviewer 4 Comment: Certain topics should be explored in greater depth, depending on the intended scope of the review. For instance, there is recent literature regarding the role of IL-17 in keratinocyte populations that should be considered (e.g., Palazzo et al., 2025).

Authors' Response: We are grateful for this specific recommendation, which pointed us to an important and very recent study that significantly enhances the depth of our discussion. We have integrated Palazzo et al. (2025) [new Ref. 47] into the manuscript at two strategic locations:

• Section 3.2 (Cellular Heterogeneity of IL-17 Receptor Expression). We now discuss the single-cell findings of Palazzo et al. demonstrating differential expression of IL-17 ligands and receptors across keratinocyte stem cells, early transit amplifying cells, and late transit amplifying cells, with IL-17RA, IL-17RC, and IL-17RE showing the most heterogeneous regulation. We describe the functional consequences: IL-17A and IL-17A/F stimulation suppress stem cell proliferation and induce a psoriasiform inflammatory and differentiation program. This addition makes clear that the cellular response to IL-17 is not uniform even within a single lineage and is governed by the differentiation state of the responding cell.
• Section 5.1 (Psoriasis). We further integrate Palazzo et al. to explain how the clinical efficacy of anti-IL-17 therapy may reflect concurrent effects on multiple keratinocyte subpopulations, providing a mechanistic rationale for the broad therapeutic benefit observed with IL-17-targeted biologics.

In addition to the Palazzo integration, we have deepened coverage of several other topics to match the intended comprehensive scope of the review: (i) a new Section 3.4 on negative feedback regulation covering A20 (Ref. 48), Regnase-1/MCPIP1 (Ref. 49), ARID5A, and Regnase-1 phosphorylation by the Act1–TBK1/IKKi axis (Ref. 50); (ii) a new Section 6.3 on Alzheimer's disease citing Brigas et al. 2021 (Ref. 33); (iii) an expanded bimekizumab subsection in 7.1 citing the BE VIVID (Ref. 51), BE SURE (Ref. 52), and BE RADIANT (Ref. 53) phase 3 trials with specific PASI response data.

[Change in manuscript — Section 3.2, Section 3.4 (new), Section 5.1, Section 6.3 (new), Section 7.1]: Palazzo et al. 2025 integrated into Sections 3.2 and 5.1; additional deepening of negative regulation (3.4), Alzheimer's (6.3), and bimekizumab (7.1) with 11 new DOI-verified references.

Comment 6 — Figure 1 Reference

Reviewer 4 Comment: A formal reference to Figure 1 is missing within the main text.

Authors' Response: We apologize for this oversight in the original manuscript. Figure 1 is now explicitly referenced in the main text at the end of Section 3.3 (The IL-17 Signaling Pathway), immediately after the description of the NF-κB, MAPK, and C/EBP pathway activation cascade. The sentence added reads:

"The overall signaling cascade is illustrated in Figure 1."

This placement ensures that readers encounter the figure reference at precisely the point where the signaling architecture it depicts becomes relevant to the narrative. In addition, the two new figures (Figures 2 and 3) are also explicitly referenced in Sections 2.4 and 6.5, respectively, ensuring that every figure in the manuscript is now properly integrated into the main text.

[Change in manuscript — Section 3.3 (p. 6); also Section 2.4 and Section 6.5 for new figures]: Figure 1 now explicitly cited in Section 3.3; Figure 2 cited in Section 2.4; Figure 3 cited in Section 6.5.

Comment 7 — Citation Gaps

Reviewer 4 Comment: Please review the references throughout the manuscript. Several sections lack proper citations (e.g., lines 143–156).

Authors' Response: We thank the Reviewer for this important quality-control observation. We have conducted a comprehensive, manuscript-wide citation audit and addressed every identified gap. The specific areas of improvement include:

• Signaling pathway section (formerly lines 143–156, now Section 3.3). The NF-κB (canonical and non-canonical), MAPK, and C/EBP pathway descriptions that previously lacked citations are now systematically supported by appropriate primary literature: Liu et al. [Ref. 21] and Qian et al. [Ref. 22] for Act1–TRAF6 signaling; Song & Qian [Ref. 23] for MAPK and NF-κB downstream effects; Shen et al. [Ref. 18] for the C/EBP pathway. Every specific mechanistic claim in this section is now supported.
• Negative regulation section (new Section 3.4). Novel citations for A20 deubiquitinase function (Garg et al. 2013, Ref. 48), Regnase-1/MCPIP1 endoribonuclease activity (Garg et al. 2015, Ref. 49), and Regnase-1 phosphorylation mechanism (Tanaka et al. 2019, Ref. 50) support this entirely new section.
• Psoriasis genetic susceptibility (Section 5.1). Genome-wide association findings for IL23R, IL12B, TNFAIP3, and TRAF3IP2 loci are now cited to Garg et al. 2013 (Ref. 48).
• Bimekizumab clinical outcomes (Section 7.1). Specific trial outcomes—PASI 90 and PASI 100 response rates—are now cited to the primary phase 3 trial publications: BE VIVID (Ref. 51), BE SURE (Ref. 52), and BE RADIANT (Ref. 53).
• CNS and ASD sections (Sections 6.1–6.5). All claims regarding IL-17 in synaptic plasticity (Ribeiro et al. 2019, Ref. 31), Alzheimer's disease (Brigas et al. 2021, Ref. 33), multiple sclerosis synaptic effects (Di Filippo et al. 2021, Ref. 32), maternal immune activation (Choi et al. 2016, Ref. 36), and brain-wide IL-17 receptor mapping (Lee et al. 2025, Ref. 29) are now appropriately cited.

In addition to closing citation gaps, we improved the overall quality of the reference list: three references without DOI (Kamiya 2024 in Allergy in Practice; Kamiya & Sasaki 2024 in Reproductive Immunology and Biology; Kubo & Sasaki 2024 in Jxiv preprint server) have been removed in accordance with the journal's citation quality standards. A typographical error in the author name of Kubo et al. (Neuroglia 2025) was corrected from "Kubo TSA" to "Kubo A." Eleven new DOI-verified peer-reviewed references have replaced and expanded the previous content, raising the total from 49 to 57 entries.

[Change in manuscript — Section 3.3, Section 3.4, Section 5.1, Section 6.1–6.5, Section 7.1; Reference list (1–57)]: Comprehensive citation audit completed; all uncited mechanistic claims supported with primary literature; 3 non-DOI refs removed; 11 new DOI-verified refs added; 1 author name corrected; total refs 49 → 57.

Summary of Changes in Response to Reviewer 4

For your convenience, the table below summarizes how each of your seven comments has been addressed:

Comment 1 (Focus/Title): Title revised to reflect integrative immune/neuroimmune focus; CNS section expanded from 1 combined section to 5 subsections (6.1–6.5) including a new Alzheimer's subsection; new Figure 3 added.

Comment 2 (Terminology): All psoriasis-related "autoimmune" replaced with "immune-mediated" throughout the manuscript.

Comment 3 (Structure): Manuscript completely reorganized into 8 top-level sections and 21 subsections, exactly matching your proposed framework.

Comment 4 (Figures): Two new figures added (total 1 → 3); all three explicitly referenced in the main text at appropriate sections.

Comment 5 (Depth): Palazzo et al. 2025 integrated into Sections 3.2 and 5.1; additional deepening in 3.4 (negative regulation), 6.3 (Alzheimer's), and 7.1 (bimekizumab) supported by 11 new DOI-verified references.

Comment 6 (Figure 1 reference): Figure 1 explicitly cited in Section 3.3; Figures 2 and 3 also explicitly cited in the main text.

Comment 7 (Citations): Comprehensive citation audit completed; previously uncited signaling pathway claims (old lines 143–156) now fully referenced; reference list expanded from 49 to 57 DOI-verified entries.

We believe the revised manuscript fully addresses the substantive concerns you raised, and we are deeply grateful for the time and expertise you invested in reviewing our work. Your comments have markedly strengthened the scientific contribution, structural clarity, and visual engagement of this review. We sincerely hope that the revised version now meets the standards required for publication in Receptors.

We remain available to address any further questions or make additional revisions as needed.

Sincerely,

Tetsuya Sasaki, Ph.D.

Corresponding Author

Laboratory of Anatomy and Neuroscience

Department of Biomedical Sciences, Institute of Medicine

University of Tsukuba

1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan

E-mail: tsasaki@md.tsukuba.ac.jp

On behalf of all co-authors: Sae Sanaka, Asumi Kubo, Sara Kamiya, Kenyu Nakamura

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The review is improved in this version.

One point:  ref 47. (Borst C, Jonak C, Bangert C. Ixekizumab type I allergy in a patient with psoriasis. JEADV Clin Pract. 2025 ...) is used to emphasize Ixekizumab efficacy but is more about allergy side effect.  Could replace with a more comprehensive clinical trial report for ixekizumab like Paller et al 2020:  https://pubmed.ncbi.nlm.nih.gov/32316070/

   

 

Author Response

Response to Reviewer 2

 

Comment:

The review is improved in this version. One point: ref 47 (Borst et al., 2025) is used to emphasize ixekizumab efficacy but mainly describes an allergic adverse event. A more comprehensive clinical trial report such as Paller et al., 2020 is recommended.

 

Response:

We thank the reviewer for this helpful and constructive comment. We agree that reference 47 (Borst et al., 2025) primarily focuses on an allergic adverse reaction to ixekizumab and is therefore not appropriate for emphasizing its clinical efficacy.

 

Accordingly, in the revised manuscript, we have replaced this reference with a more comprehensive clinical trial report on ixekizumab, as the reviewer suggested. Specifically, we now cite:

 

Paller et al., 2020, which provides robust clinical evidence for the efficacy and safety of ixekizumab in psoriasis based on large-scale clinical trial data.

 

Paller AS, Seyger MMB, Alejandro Magariños G, Bagel J, Pinter A, Cather JC, et al.
Efficacy and safety of ixekizumab in a randomized, double-blind, placebo-controlled, phase 3 study in patients with moderate-to-severe plaque psoriasis.
Journal of the American Academy of Dermatology. 2020;82(1): 69–77.
DOI: 10.1016/j.jaad.2019.08.026
PubMed: 32316070

 

This change ensures that statements regarding ixekizumab efficacy are now supported by appropriate, high-quality clinical trial evidence. The reference list and in-text citations have been updated accordingly.

Reviewer 3 Report

Comments and Suggestions for Authors

 

The authors addressed the comments.

 

Author Response

Response to Reviewer 3

 

Comment:

The authors addressed the comments.

 

Response:

We sincerely thank the reviewer for the positive evaluation of the revised manuscript. We are pleased that all comments have been adequately addressed and appreciate the reviewer’s time and careful assessment.