How Does Maternal Immune Activity Affect Fetal Survival and Brain Development? The Critical Roles of IL-17A and Microglia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review is comprehensive and current, which summarizes recent findings on the effects of maternal immune activation (MIA) on fetal survival and microglial phenotype. Studies using poly(I:C)-induced MIA mouse models have revealed a crucial role for IL-17A in mediating these effects. Overexpression of RORγt enhances poly(I:C)-induced fetal loss. Intraventricular administration of IL-17A in fetal brains activates microglia and alters their localization, particularly in periventricular regions and the medial cortex. These activated microglia may lead to long-term neurodevelopmental abnormalities. The authors addressed important clinical implications, including the potential for early identification of high-risk pregnancies and the development of novel preventive and therapeutic strategies.

 

The article is articulately written; however, several references were cited in the text without a number, but with the first author and the year of publication. Please be consistent throughout the manuscript.

Author Response

We thank the editors and reviewers for their encouraging and helpful comments on our manuscript. We have made our best effort in revising our manuscript to answer all the points raised by the reviewers. Our point-by-point responses to the comments are as follows.

We thank the reviewer for the positive evaluation of our manuscript and for pointing out the inconsistency in citation style. In accordance with the reviewer’s comment, we have carefully reviewed all in-text citations and revised them to ensure full consistency with the Neuroglia (MDPI) reference format. Specifically, lines 160–161 and 164–165 on page 4 have been revised (marked in red). All citations now appear in numbered form [1], [2], etc., rather than using the “Author et al., Year” style. We also cross-checked that each numbered citation corresponds correctly to the reference list, following the order of appearance in the text. This revision ensures stylistic uniformity and compliance with the journal’s formatting guidelines.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The article is a review focused on the role of IL-17A and microglia in the mechanisms by which maternal immune activation (MIA) affects fetal survival and brain development.
The authors summarize data on the interactions between maternal cytokines, the placental IL-17A/IL-17RA axis, and fetal microglia.
The manuscript is timely and informative, addressing both mechanistic and clinical aspects, including a cross-level analysis of data from animal models, organoids, and clinical studies.
Nevertheless, the work requires substantial revision to improve clarity, structural logic, and practical value.

Strengths

• Well-structured presentation of the key mediators of MIA (IL-6, IL-17A) and the role of microglia.
• Detailed discussion of preclinical models, including PRIMA-17, NHP models, and organoids.
• Integration of the DOHaD concept and translational biomarkers.
• Support for recommendations on standardization of MIA research (checklist in Section 15).

Recommendations

1. Focus the main text on the core IL-17A–microglia–placenta axis and clearly separate the key conclusions from background information.
2. Add a comparative analysis of IL-17A and other cytokines (IL-6, TNF-α), highlighting discrepancies in the literature and unresolved questions.
3. Discuss in more detail the translational limitations: interspecies differences, applicability of doses and time windows to humans.
4. Expand the discussion of potential risks and ethical considerations related to interventions targeting the IL-17A signaling pathway during pregnancy.
5. Restructure the manuscript so that, after the introduction, the following sections appear:
   I. Placental mechanisms
   II. Microglia and brain development
   III. Clinical correlates and biomarkers
   IV. Translation and future perspectives
6. Reduce repetitive references to the same experiments (e.g., Choi et al., 2016).
7. Add schematic figures/graphics to improve comprehension:
• windows of vulnerability,
• the MIA–IL-17A–microglia–fetal brain signaling pathway,
• potential points for therapeutic intervention.
8. Undertake language editing to eliminate unnecessarily complex sentence structures and improve readability.

Author Response

Responses to Decision Letter

 

We thank the reviewers for their encouraging and helpful comments on our manuscript. We have made our best effort in revising our manuscript to answer all the points raised by the reviewers. Our point-by-point responses to the comments are as follows.

 

Responses to Reviewer #2

 

General Comment: The article is a review focused on the role of IL-17A and microglia in the mechanisms by which maternal immune activation (MIA) affects fetal survival and brain development. The authors summarize data on the interactions between maternal cytokines, the placental IL-17A/IL-17RA axis, and fetal microglia. The manuscript is timely and informative, addressing both mechanistic and clinical aspects, including a cross-level analysis of data from animal models, organoids, and clinical studies. Nevertheless, the work requires substantial revision to improve clarity, structural logic, and practical value.

Strengths

1. Well-structured presentation of the key mediators of MIA (IL-6, IL-17A) and the role of microglia.
2. Detailed discussion of preclinical models, including PRIMA-17, NHP models, and organoids.
3. Integration of the DOHaD concept and translational biomarkers.
4. Support for recommendations on standardization of MIA research (checklist in Section 15).

 

Response: We sincerely thank you for your thorough and constructive review of our manuscript. We greatly appreciate your recognition of the strengths of our work, particularly the comprehensive presentation of MIA mediators, the detailed discussion of preclinical models, and the integration of the DOHaD framework with translational biomarkers. We are grateful for your acknowledgment that our manuscript is timely and informative, addressing both mechanistic and clinical aspects through a cross-level analysis. Your positive comments regarding our structured presentation of IL-6 and IL-17A as key mediators, as well as our discussion of various model systems including PRIMA-17, NHP models, and organoids, are especially encouraging.

We fully agree with your assessment that the manuscript would benefit from substantial revision to enhance clarity, structural logic, and practical value. We have carefully considered all your specific recommendations and have implemented comprehensive revisions accordingly.

 

Comment 2: Focus the main text on the core IL-17A–microglia–placenta axis and clearly separate the key conclusions from background information.

 

Response 2: We thank the reviewer for this valuable suggestion. In accordance with the recommendation, we have refined the manuscript to emphasize the IL-17A–microglia–placenta axis as the central mechanistic theme linking maternal immune activation (MIA) to both fetal loss and neurodevelopmental outcomes. Specifically:

1. Introduction:

We inserted a new focus statement at the beginning of the Introduction (page 1, line 40– page 2, line 48) explicitly defining the IL-17A–microglia–placenta axis as the conceptual framework of this review. The surrounding paragraphs were lightly edited so that background information on MIA now serves primarily to contextualize this axis rather than to broaden the scope.

12.Clinical Implications and Future Directions:

At the start of this section (page 12, lines 389–391), we added a summarizing sentence—

“Integrating the evidence reviewed above, the IL-17A–microglia–placenta axis emerges as a pivotal target for preventive and therapeutic strategies against MIA-induced disorders.”

—to re-establish the central focus and ensure thematic continuity from mechanistic to translational discussion.

 

Through these revisions, the manuscript now consistently highlights how IL-17A-driven placental dysregulation and microglial activation form a unified pathway underlying MIA-related fetal and neurodevelopmental pathology, while clearly distinguishing core conclusions from contextual background.

 

Comment 2: Add a comparative analysis of IL-17A and other cytokines (IL-6, TNF-α), highlighting discrepancies in the literature and unresolved questions.

 

Response 2: We appreciate this constructive suggestion. In response, we have added the mechanistic section (Section 7. Comparative Roles of IL-17A, IL-6, and TNF-α in Maternal Immune Activation) to include a comparative analysis of IL-17A, IL-6, and TNF-α in the context of MIA. This new paragraph (page 5, lines 205–227) summarizes their distinct but interacting roles in maternal–fetal signaling and clarifies inconsistencies among published studies.

Specifically:

Comparative Summary Added: A new paragraph now contrasts IL-17A’s placenta-to-brain signaling pathway with the systemic inflammatory effects of IL-6 and TNF-α. We highlight that IL-6 predominantly influences neurogenesis and gliogenesis, TNF-α regulates apoptotic balance and endothelial activation, while IL-17A acts more directly on placental and microglial compartments.

Discussion of Discrepancies and Unresolved Issues: The new text notes that differences in experimental design (e.g., timing, cytokine combinations, and receptor expression profiles) contribute to variability across studies. It also identifies unresolved questions regarding cytokine synergy, threshold effects, and species-specific responses.

These changes address the reviewer’s comment by positioning IL-17A within a broader cytokine network while retaining the manuscript’s focus on the IL-17A–microglia–placenta axis.

 

Comment 3: Discuss in more detail the translational limitations: interspecies differences, applicability of doses and time windows to humans.

 

Response 3: We thank the reviewer for emphasizing the importance of translational considerations.

In the revised manuscript, we have added a new paragraph titled “Translational Limitations and Species-Specific Considerations” within Section 12. Clinical Implications and Future Directions section (page 12, lines –398-410 shown in red).

This addition explicitly discusses the major factors limiting direct extrapolation of rodent and non-human primate data to human pregnancy, including:

(1) structural and immunological species differences in the placenta and cytokine receptor expression (IL-17RA, IL-6R, TNFR);

(2) discrepancies in MIA dosing paradigms and gestational timing relative to human development;

(3) genetic and environmental heterogeneity in human populations; and

(4) potential safety and timing challenges for cytokine-targeted interventions.

We also propose humanized mouse models and placental organoid systems as potential tools to overcome these limitations.This revision provides a balanced and realistic assessment of translational relevance, addressing the reviewer’s concern while maintaining the manuscript’s overall focus on the IL-17A–microglia–placenta axis.

 

Comment 4: Expand the discussion of potential risks and ethical considerations related to interventions targeting the IL-17A signaling pathway during pregnancy.

 

Response 4: We appreciate the reviewer’s insightful comment. In the revised manuscript, we have explicitly expanded the Section 12, Clinical Implications and Future Directions, to address the safety risks and ethical considerations associated with targeting the IL-17A signaling pathway during pregnancy (page 12, lines –414-431 shown in blue)

Specifically, the revised paragraph discusses:

(i) the potential risk of compromised host defense and reduced vaccine responsiveness,

(ii) possible disruption of placental immune tolerance and maternal–fetal immune homeostasis,

(iii) potential long-term impacts on fetal immune maturation and neurodevelopment,

(iv) key aspects of clinical trial design, including dosing, timing, and eligibility criteria, and

(v) the importance of ethical oversight, including informed consent, independent ethics review, adverse-event monitoring, and pregnancy registry participation.

Together, these revisions integrate safety and ethical considerations into the translational discussion, providing a balanced framework for evaluating IL–17A–targeted interventions during pregnancy.

 

Comment 5: Restructure the manuscript so that, after the introduction, the following sections appear:

1. Placental mechanisms
2. Microglia and brain development

III. Clinical correlates and biomarkers

1. Translation and future perspectives

 

Response 5:

Thank you for this helpful suggestion. To improve structural clarity without changing the existing section order or numbering, we inserted the following roadmap sentence at the end of the Introduction:

 

“This review is organized into four conceptual parts: (I) Placental Mechanisms, (II) Microglia and Brain Development, (III) Clinical Correlates and Biomarkers, and (IV) Translational Perspectives and Future Directions.” (page 2, lines 92-94)

 

Comment 6: Reduce repetitive references to the same experiments (e.g., Choi et al., 2016).

 

Response 6: We thank the reviewer for this helpful observation. In the revised manuscript, we have carefully reviewed all mentions of Choi et al., 2016 (Science, 351:933–939) and other frequently cited key studies to ensure that each reference appears only where it adds distinct scientific context.

Specifically, we have:

Consolidated redundant citations of Choi et al., 2016 in the sections discussing IL-17A’s role in cortical malformation and ASD-like behavior. The main findings of this study—maternal IL-17A induction, the rescue of behavioral abnormalities by anti-IL-17A treatment, and the replication of ASD-like features by direct fetal IL-17A injection—are now summarized once in the mechanistic section (Effects of MIA on Fetal Brain Development), with cross-references rather than repeated in subsequent paragraphs.

Removed duplications in later sections where the same experiment was previously re-explained. Related mechanistic discussions (e.g., microglial activation, cortical patch formation) now refer readers to the consolidated description using “as demonstrated by Choi et al. [24]” or equivalent phrasing.

Through these adjustments, the manuscript avoids redundancy, maintains scientific rigor, and presents a clearer and more streamlined narrative regarding the mechanistic role of IL-17A in MIA-induced neurodevelopmental abnormalities.

 

Comment 7: Add schematic figures/graphics to improve comprehension: windows of vulnerability, the MIA–IL-17A–microglia–fetal brain signaling pathway, potential points for therapeutic intervention.

 

Response 7: We thank the reviewer for the constructive suggestion to include schematic figures that enhance comprehension of the manuscript’s key concepts. In accordance with this recommendation, we have added Figure 2, “Windows of Vulnerability to Maternal Immune Activation (MIA),” in Section 3 (Critical Windows of Susceptibility).

This figure illustrates the developmental timing of MIA susceptibility by aligning mouse embryonic days (E) with approximate human gestational weeks, highlighting the mid-gestational period (E12.5–E14; ≈10–18 weeks in humans) as the peak window of vulnerability. It visually summarizes the overlap between cortical neurogenesis, microglial colonization, and IL-17A signaling, which defines the critical developmental stage when maternal immune activation has the most significant impact on fetal neurodevelopment.

We believe this figure improves conceptual clarity and provides readers with a visual framework for understanding the temporal aspects of MIA-related vulnerability. Additional schematic figures (the MIA–IL-17A–microglia–fetal brain pathway and therapeutic intervention points) were also prepared following the reviewer’s suggestion to enhance overall comprehension.

Fig 2. Windows of Vulnerability to Maternal Immune Activation (MIA)

Schematic alignment of mouse embryonic development with approximate human gestation. The mid-gestational period (E12.5–E14 in mice; approximately 10–18 weeks in humans) represents the peak window of susceptibility to maternal immune activation (MIA). During this phase, overlapping corticogenesis (E10–E16) and microglial colonization render the fetal brain highly sensitive to IL-17A signaling, which can alter neuronal migration and cortical patterning. Earlier stages correspond to implantation and placental development, whereas later stages (E16–P14) coincide with synaptogenesis and astrocyte maturation, influencing circuit refinement and gliogenesis.

 

Comment 8: Undertake language editing to eliminate unnecessarily complex sentence structures and improve readability.

 

Response 8: We agree and have undertaken comprehensive language editing. Long and complex sentences have been eliminated, and the manuscript has been professionally edited for improved readability.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have done a good job addressing the comments, and the article may be accepted for publication.

Good luck!