Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

Dear authors, this topic is of highest interest. However, I have some comments to make.

Your introduction I comprehensive, but the aim of your review is not very clear. What is the main question of your review? What is the gap in the literature that you want to cover?

It looks like a narrative review, but this is not clearly stated by the authors. Also how did you make the search for the relevant articles? How did you choose them, what was the criteria?

You talk about decidual macrophages, but you do not mention Hofbauer cells. I think there is a cross-talk between maternal and fetal immune system in the placenta.

Also in this comprehensive review, the role of autophagy is not mentioned.

Inflammation is primarily linked to premature birth, rupture of membranes, chorioamniotitis, which are not mentioned here. Maybe you should specify exactlty what you want to explore.

 Regarding therapies, in table 1 you should add references.

Section 8 : Exosomal Signaling at the Maternal–Fetal Interface: Orchestrating Im mune and Vascular Adaptation. I am not sure what is its relevance in this review.If you want to keep it you should move this section to future perspective.

 The conclusions are not linked to the title of this review.

Please revise your manuscript.

Author Response

25  March 2026

 

Dear Dr. Maureen Mao

Editor

International Journal of Molecular Sciences

 

Re: Manuscript reference number: [ijms-4111939]

 

“The Inflammatory Landscape of Pregnancy: Maternal–Fetal Immunity, Basis for Disease, and Targeted Treatments”

 

We would like to thank the editor and the reviewers for their careful evaluation of our manuscript and for their constructive comments, which have been extremely helpful in improving the quality, clarity, and clinical relevance of this case report.

 

In response to these comments, we have revised the manuscript, accordingly, addressing all points raised and expanding relevant sections as suggested. Below, we provide a point-by-point response to the Editor’s and Reviewers’ comments. All modifications have been incorporated into the revised manuscript, with changes highlighted in bold, and page and line numbers indicated as requested.

 

Reviewer # 1.

 

Reviewer 1, comment 1: The objective of your review is not very clear. What is the main question? What gap in the literature are you addressing?

 

1. Reply to reviewer 1, comment 1: We thank the reviewer for this important and constructive comment. In response, we have revised the final section of the Introduction (page 3, lines 114-128 ) to more clearly articulate the objective and scope of the review. The revised text now explicitly states that the aim of this review is to provide an integrated synthesis of current evidence on how dysregulated inflammatory signaling at the maternal–fetal interface contributes to placental dysfunction and systemic endothelial injury.

 

We also clarified the conceptual gap addressed by this review, namely the lack of a unified framework that integrates immune dysregulation, angiogenic imbalance, and endothelial dysfunction as interconnected mechanisms underlying placental-mediated pregnancy complications, particularly fetal growth restriction and hypertensive placental disorders. By framing these processes within a shared pathophysiological continuum, the review aims to bridge molecular, translational, and clinical perspectives and to highlight emerging therapeutic targets.

 

2. Modification in the text (page 3, lines114-128 ): Despite substantial progress in placental immunology, critical gaps remain in understanding how immune dysregulation at the maternal–fetal interface translates into placental insufficiency and systemic endothelial dysfunction [15,16,28]. Fetal growth restriction and hypertensive pregnancy disorders are frequently considered separate clinical entities, yet accumulating evidence suggests that both emerge from converging inflammatory and angiogenic disturbances within the placenta [8,10,17,18]. Defective spiral artery remodeling, placental ischemia, and the release of antiangiogenic and proinflammatory mediators—including sFlt-1, soluble endoglin, IL-6, and TNF-α—link local placental pathology to systemic maternal vascular dysfunction [37,38].

For these reasons, this review focuses primarily on fetal growth restriction and hypertensive placental disorders as clinically relevant models of inflammation-driven placental disease. By synthesizing current evidence on inflammatory signaling at the maternal–fetal interface, we aim to integrate molecular mechanisms, biomarkers, and emerging therapeutic strategies to improve pregnancy outcomes and reduce global disparities in maternal and neonatal health.

 

Reviewer 1, comment 2: This appears to be a narrative review, but this is not clearly stated. How was the search performed?

 

Reply to reviewer 1, comment 2:  We thank the reviewer for this helpful observation. In response, we have clarified in the Methods section that the manuscript is structured as a narrative literature review. We have also expanded the methodology to provide greater transparency regarding the literature search and study selection process.

 

Specifically, we now describe the databases consulted (PubMed/MEDLINE and Scopus), the time frame of the search (January 1989 to November 2025), and the key search terms used, including combinations of terms related to placental inflammation, fetal growth restriction, hypertensive placental disorders, cytokines, inflammasomes, endothelial dysfunction, and maternal–fetal immune interactions. We further clarify the general eligibility criteria, the screening process (title, abstract, and full-text review), and the principles guiding article selection based on relevance, methodological rigor, and translational significance.

 

Modification in the text (Page 3 – 5): The Methodology section has been expanded to explicitly describe the literature search strategy, eligibility criteria, and study selection process.

 

Reviewer 1, Comment 3: You mention decidual macrophages but not Hofbauer cells.

 

Reply to reviewer 1, comment 3: We thank the reviewer for this insightful suggestion. The revised manuscript now incorporates a discussion of Hofbauer cells, highlighting their emerging role in fetoplacental immune crosstalk and inflammatory signaling. This addition enhances the description of bidirectional immune interactions at the maternal–fetal interface and further contextualizes the contribution of fetal-derived immune cells to placental immune regulation.

 

Modification in the manuscript: Changes were introduced in page 7, lines 264-287, where the section on Hofbauer cells was expanded and refined to incorporate their role in fetoplacental immune crosstalk, innate immune defense, and inflammatory signaling. The revised text also highlights emerging evidence linking alterations in CD74-mediated signaling with the pro-inflammatory polarization of Hofbauer cells and its potential contribution to placental dysfunction in fetal growth restriction and hypertensive placental disorders.

 

Reviewer 1, comment 4: The role of autophagy is not mentioned.

 

Reply to reviewer 1, comment 4: We thank the reviewer for this valuable observation. In response, we have added a dedicated subsection discussing the role of autophagy in placental stress responses and inflammatory signaling. The revised text highlights the role of autophagy in maintaining trophoblast homeostasis, its interaction with hypoxic and oxidative stress pathways, and its crosstalk with inflammasome activation and inflammatory signaling in placental disease.

 

These additions strengthen the mechanistic framework of the review by integrating autophagy as a key regulatory pathway linking placental stress, inflammatory activation, and endothelial dysfunction.

 

Modification in the manuscript: A new subsection titled “Autophagy and Placental Stress Responses in Preeclampsia” has been incorporated on page 10, lines 439-471 .

 

Reviewer 1, comment 5: Inflammation is mainly related to preterm birth, rupture of membranes, and chorioamnionitis, which are not mentioned.

 

Reply reviewer 1, comment 5: We thank the reviewer for this thoughtful comment and agree that inflammatory processes are well recognized in the context of spontaneous preterm birth, premature rupture of membranes, and chorioamnionitis, where infection-related inflammatory pathways play a central role.  However, the primary aim of this review is to explore inflammation in the context of placental dysfunction, particularly as it relates to fetal growth restriction and preeclampsia. Our intention is therefore not to comprehensively cover all obstetric conditions associated with inflammation, but rather to examine how immune dysregulation at the maternal–fetal interface contributes to placental-mediated disease.

 

To clarify this scope, we have revised the Introduction to explicitly state that the review focuses on preeclampsia and fetal growth restriction as prototypical models of inflammation-driven placental pathology, where immune imbalance, angiogenic disruption, and endothelial dysfunction converge. We believe this clarification helps define the conceptual framework of the review while acknowledging the broader role of inflammation in other obstetric conditions.

 

Modification in the manuscript (Page 2, Lines 60-73): The scope of the review has been clarified in the Introduction, where we now explicitly state that the discussion focuses on preeclampsia and fetal growth restriction as models of inflammation-related placental dysfunction.

 

Reviewer 1, comment 6: Table 1 should include references.

 

Reply to reviewer 1, comment 6: We thank the reviewer for this helpful suggestion. References supporting the information presented in Table 1 have now been added to the revised manuscript.

 

Reply to reviewer 1, comment 7: Section 8 (Exosomal signaling)… move to future perspectives.

 

Reply to reviewer 1, comment 7: We thank the reviewer for this helpful suggestion. Section 8 (Exosomal signaling) has been moved to the Future Perspectives section in the revised manuscript.

 

Reviewer 1, comment 8: The conclusions are not linked to the title.

 

Reply to reviewer 1, comment 8: We thank the reviewer for this constructive suggestion. The Conclusion section has been revised to more clearly reflect the central theme of the review, namely the inflammatory landscape of pregnancy and its role in linking maternal–fetal immune regulation with placental dysfunction and vascular disease. The revised text now explicitly connects immune dysregulation at the maternal–fetal interface with the development of placental-mediated complications and highlights the implications for future targeted therapeutic strategies.

 

Reviewer # 2.

Reviewer 2 comment 1: The review would benefit from deeper coverage of molecular mechanisms and immune cell interactions.

Reply to reviewer 2, comment 1: We thank the reviewer for this valuable suggestion. In response, the manuscript has been revised to further expand the discussion of molecular mechanisms and immune cell interactions at the maternal–fetal interface. Additional content has been incorporated addressing the roles of innate and adaptive immune populations, inflammasome signaling, cytokine networks, and angiogenic pathways, as well as their interactions with trophoblast biology and endothelial function. We incorporated a more detailed discussion of Th17 cells, B cells (including AT1-AA production), macrophage polarization, neutrophil participation, and their integration within the NLRP3 inflammasome cascade. In addition, we introduced a new subsection (Section 4.1) that addresses autophagy and its interactions with placental stress and inflammasome activation. These additions strengthen the mechanistic framework of the review and better integrate molecular and cellular insights into the pathophysiology of placental-mediated pregnancy disorders.

Modification in the manuscript: Relevant sections throughout the manuscript have been expanded to provide a more detailed discussion of immune cell dynamics and molecular inflammatory pathways involved in placental dysfunction.

Reviewer 2 comment 2: Figure 1 is small, incomplete, and unclear regarding immune interactions and marker expression.

Reply to reviewer 2, comment 2: Figure 1 has been substantially revised to improve both conceptual and visual representation. The updated figure now clearly delineates the maternal and fetal compartments, specifies the CD56^bright^CD16⁻ decidual NK phenotype, and illustrates key cytokine-mediated interactions among NK cells, macrophages, dendritic cells, and Tregs at the maternal-fetal interface. In addition, galectin signaling (Gal-1 and Gal-9) and relevant immune checkpoint interactions have been incorporated to better reflect current understanding of immunoregulatory mechanisms in placental biology. The overall graphical layout and color scheme were also refined to improve readability, structural balance, and interpretability of the immune interactions depicted. The graphic layout and color coding were improved to enhance clarity and balance.

Modification in the manuscript: Figure 1.

Reviewer 2 comment 3: Expand discussion of B cells, Th17 cells, dendritic cells, neutrophils, and MDSCs.

Reply to reviewer 2, comment 3: We thank the reviewer for this valuable suggestion. In the revised manuscript, we have expanded the discussion of additional immune cell populations at the maternal–fetal interface, including B cells, Th17 cells, dendritic cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), to provide a more comprehensive overview of the immune interactions contributing to placental inflammation and immune regulation.

Reviewer 2 comment 4: The role of galectins requires more detailed discussion and inclusion in figures.

Reply to reviewer 2, comment 4: We thank the reviewer for this important suggestion. In the revised manuscript, the figures have been updated, and the corresponding sections expanded to provide a more detailed discussion of this topic and its relevance to placental dysfunction and immune dysregulation at the maternal–fetal interface. Section 2.2 has been substantially expanded to include a detailed mechanistic discussion of Galectin-1 and Galectin-9, including glycan-mediated signaling, TIM-3 interactions, Treg modulation, and effects on spiral artery remodeling. Galectin dysregulation has also been incorporated into the redesigned Figure 1 and integrated into the updated final model (Figure 5), highlighting its contribution to immune tolerance and vascular adaptation.

Reviewer 2 comment 5: Improve Figure 2 (more informative and visual).

Reply to reviewer 2, comment 5: Figure 2 has been substantially redesigned to depict a molecular interaction network highlighting inflammasome activation and the reciprocal signaling among Th17 cells, macrophages, neutrophils, B cells, and regulatory T cells. The revised illustration emphasizes cytokine-driven amplification loops and immune cell crosstalk, thereby enhancing both the mechanistic coherence and visual clarity of the pathways implicated in inflammatory placental dysfunction.

Modification in the manuscript: Figure 2.

Reviewer 2 comment 6: Figure 5 lacks logical sequence and clear cause–effect relationships.

Reply to reviewer 2 comment 6: Figure 5 has been restructured into an integrated cascade model linking placental stress responses to key downstream molecular events, including NLRP3 inflammasome activation, dysregulation of galectin signaling, impaired autophagy, and angiogenic imbalance (sFlt-1, sEng, and PlGF), ultimately leading to maternal endothelial dysfunction. The revised figure now more clearly depicts the cause-and-effect relationships across these interconnected pathways, culminating in the clinical manifestations of preeclampsia and fetal growth restriction.

Modification in the manuscript: Figure 5.

Reviewer 2 comment 7: Add additional information on Galectin-9 and expand Treg discussion.

Reply to reviewer 2, comment 7: We thank the reviewer for this valuable suggestion. In the revised manuscript, we have expanded the discussion of Galectin-9 signaling via the TIM-3 pathway, highlighting its role in regulating NK cell activity and promoting regulatory T cell (Treg) expansion at the maternal–fetal interface. In addition, we incorporated a dedicated subsection on regulatory T cells, emphasizing their central role in maintaining immune tolerance and controlling inflammatory responses during pregnancy. The revised text further discusses how Treg dysfunction may contribute to endothelial injury, angiogenic imbalance, and the development of placental-mediated complications.

We hope these revisions adequately address your concerns. Please feel free to provide further guidance if you believe additional improvements are needed.

 

Once again, we appreciate your time and valuable input.

 

Sincerely,

 

 

Jezid Miranda, MD, PhD

Department of Obstetrics and Gynecology, Universidad de Cartagena

Cartagena de Indias, Colombia

Telephone: + 57 3014238444

jmirandaq@unicartagena.edu.co

Twitter: @JezidMiranda

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This review focuses on the immune mechanisms of inflammation in preeclampsia.
This topic is relevant, as is coverage of current and developing approaches to treating this life-threatening condition.
The review covers over 140 literature sources; however, in some areas, more depth and coverage of known or hypothetical molecular mechanisms of pathology development, as well as the interactions of individual "participants" of immune processes in normal and pathological pregnancy, would have been appreciated. The journal's title requires this.
The reviewer had the following comments:
Figure 1 - The figure is very small and incomplete. It is also unclear what the different colors mean, or what the separate expression of CD56 and CD16 on NK cells signifies. The figure appears unbalanced and asymmetrical, making it difficult to understand. The cytokines mediating the effects and the interactions between different cell populations are not specified. The graphic design of the figure requires improvement.

Line 131 – A more detailed discussion of the roles of B cells, Th17 cells, dendritic cells, and neutrophils in inflammation during preeclampsia would be useful. The role of the suppressor MDSC population, whose immunosuppressive function is important for maintaining pregnancy and is weakened in preeclampsia, is also not covered (doi: 10.3389/fimmu.2023.1080391; https://doi.org/10.1016/j.jri.2018.05.002).
Line 192 – The role of galectins in tolerance formation and their role in cellular interactions is not described in detail. The role of galectin/glycan abnormalities in the development of preeclampsia (doi: 10.3390/ijms20133192
doi: 10.3389/fimmu.2022.1088024
https://pmc.ncbi.nlm.nih.gov/articles/PMC6593412/
https://pmc.ncbi.nlm.nih.gov/articles/PMC12370818/
https://doi.org/10.3389/fimmu.2021.784473
https://doi.org/10.3390/medicina58020157
These points also need to be added to Figure 1.
Figure 2 - Make the figure more informative (more detailed) and more visual.
Figure 5 - The figure looks It's illogical; the sequence of interactions is lost. The drawing is completely unclear and incomplete. It's necessary to graphically highlight cause and effect, and balance the individual fragments of the drawing by size.
Line 429 – add information about galectins
Section 7 – information on the effects of galectin 9 can be added (doi: 10.3389/fimmu.2018.03142).
Line 541 – add reference
Section 7.3.3 – information on Tregs can be added (doi.org/10.3389/fimmu.2019.00478)

Author Response

25  March 2026

 

Dear Dr. Maureen Mao

Editor

International Journal of Molecular Sciences

 

Re: Manuscript reference number: [ijms-4111939]

 

“The Inflammatory Landscape of Pregnancy: Maternal–Fetal Immunity, Basis for Disease, and Targeted Treatments”

 

We would like to thank the editor and the reviewers for their careful evaluation of our manuscript and for their constructive comments, which have been extremely helpful in improving the quality, clarity, and clinical relevance of this case report.

 

In response to these comments, we have revised the manuscript, accordingly, addressing all points raised and expanding relevant sections as suggested. Below, we provide a point-by-point response to the Editor’s and Reviewers’ comments. All modifications have been incorporated into the revised manuscript, with changes highlighted in bold, and page and line numbers indicated as requested.

 

Reviewer # 1.

 

Reviewer 1, comment 1: The objective of your review is not very clear. What is the main question? What gap in the literature are you addressing?

 

1. Reply to reviewer 1, comment 1: We thank the reviewer for this important and constructive comment. In response, we have revised the final section of the Introduction (page 3, lines 114-128 ) to more clearly articulate the objective and scope of the review. The revised text now explicitly states that the aim of this review is to provide an integrated synthesis of current evidence on how dysregulated inflammatory signaling at the maternal–fetal interface contributes to placental dysfunction and systemic endothelial injury.

 

We also clarified the conceptual gap addressed by this review, namely the lack of a unified framework that integrates immune dysregulation, angiogenic imbalance, and endothelial dysfunction as interconnected mechanisms underlying placental-mediated pregnancy complications, particularly fetal growth restriction and hypertensive placental disorders. By framing these processes within a shared pathophysiological continuum, the review aims to bridge molecular, translational, and clinical perspectives and to highlight emerging therapeutic targets.

 

2. Modification in the text (page 3, lines114-128 ): Despite substantial progress in placental immunology, critical gaps remain in understanding how immune dysregulation at the maternal–fetal interface translates into placental insufficiency and systemic endothelial dysfunction [15,16,28]. Fetal growth restriction and hypertensive pregnancy disorders are frequently considered separate clinical entities, yet accumulating evidence suggests that both emerge from converging inflammatory and angiogenic disturbances within the placenta [8,10,17,18]. Defective spiral artery remodeling, placental ischemia, and the release of antiangiogenic and proinflammatory mediators—including sFlt-1, soluble endoglin, IL-6, and TNF-α—link local placental pathology to systemic maternal vascular dysfunction [37,38].

For these reasons, this review focuses primarily on fetal growth restriction and hypertensive placental disorders as clinically relevant models of inflammation-driven placental disease. By synthesizing current evidence on inflammatory signaling at the maternal–fetal interface, we aim to integrate molecular mechanisms, biomarkers, and emerging therapeutic strategies to improve pregnancy outcomes and reduce global disparities in maternal and neonatal health.

 

Reviewer 1, comment 2: This appears to be a narrative review, but this is not clearly stated. How was the search performed?

 

Reply to reviewer 1, comment 2:  We thank the reviewer for this helpful observation. In response, we have clarified in the Methods section that the manuscript is structured as a narrative literature review. We have also expanded the methodology to provide greater transparency regarding the literature search and study selection process.

 

Specifically, we now describe the databases consulted (PubMed/MEDLINE and Scopus), the time frame of the search (January 1989 to November 2025), and the key search terms used, including combinations of terms related to placental inflammation, fetal growth restriction, hypertensive placental disorders, cytokines, inflammasomes, endothelial dysfunction, and maternal–fetal immune interactions. We further clarify the general eligibility criteria, the screening process (title, abstract, and full-text review), and the principles guiding article selection based on relevance, methodological rigor, and translational significance.

 

Modification in the text (Page 3 – 5): The Methodology section has been expanded to explicitly describe the literature search strategy, eligibility criteria, and study selection process.

 

Reviewer 1, Comment 3: You mention decidual macrophages but not Hofbauer cells.

 

Reply to reviewer 1, comment 3: We thank the reviewer for this insightful suggestion. The revised manuscript now incorporates a discussion of Hofbauer cells, highlighting their emerging role in fetoplacental immune crosstalk and inflammatory signaling. This addition enhances the description of bidirectional immune interactions at the maternal–fetal interface and further contextualizes the contribution of fetal-derived immune cells to placental immune regulation.

 

Modification in the manuscript: Changes were introduced in page 7, lines 264-287, where the section on Hofbauer cells was expanded and refined to incorporate their role in fetoplacental immune crosstalk, innate immune defense, and inflammatory signaling. The revised text also highlights emerging evidence linking alterations in CD74-mediated signaling with the pro-inflammatory polarization of Hofbauer cells and its potential contribution to placental dysfunction in fetal growth restriction and hypertensive placental disorders.

 

Reviewer 1, comment 4: The role of autophagy is not mentioned.

 

Reply to reviewer 1, comment 4: We thank the reviewer for this valuable observation. In response, we have added a dedicated subsection discussing the role of autophagy in placental stress responses and inflammatory signaling. The revised text highlights the role of autophagy in maintaining trophoblast homeostasis, its interaction with hypoxic and oxidative stress pathways, and its crosstalk with inflammasome activation and inflammatory signaling in placental disease.

 

These additions strengthen the mechanistic framework of the review by integrating autophagy as a key regulatory pathway linking placental stress, inflammatory activation, and endothelial dysfunction.

 

Modification in the manuscript: A new subsection titled “Autophagy and Placental Stress Responses in Preeclampsia” has been incorporated on page 10, lines 439-471 .

 

Reviewer 1, comment 5: Inflammation is mainly related to preterm birth, rupture of membranes, and chorioamnionitis, which are not mentioned.

 

Reply reviewer 1, comment 5: We thank the reviewer for this thoughtful comment and agree that inflammatory processes are well recognized in the context of spontaneous preterm birth, premature rupture of membranes, and chorioamnionitis, where infection-related inflammatory pathways play a central role.  However, the primary aim of this review is to explore inflammation in the context of placental dysfunction, particularly as it relates to fetal growth restriction and preeclampsia. Our intention is therefore not to comprehensively cover all obstetric conditions associated with inflammation, but rather to examine how immune dysregulation at the maternal–fetal interface contributes to placental-mediated disease.

 

To clarify this scope, we have revised the Introduction to explicitly state that the review focuses on preeclampsia and fetal growth restriction as prototypical models of inflammation-driven placental pathology, where immune imbalance, angiogenic disruption, and endothelial dysfunction converge. We believe this clarification helps define the conceptual framework of the review while acknowledging the broader role of inflammation in other obstetric conditions.

 

Modification in the manuscript (Page 2, Lines 60-73): The scope of the review has been clarified in the Introduction, where we now explicitly state that the discussion focuses on preeclampsia and fetal growth restriction as models of inflammation-related placental dysfunction.

 

Reviewer 1, comment 6: Table 1 should include references.

 

Reply to reviewer 1, comment 6: We thank the reviewer for this helpful suggestion. References supporting the information presented in Table 1 have now been added to the revised manuscript.

 

Reply to reviewer 1, comment 7: Section 8 (Exosomal signaling)… move to future perspectives.

 

Reply to reviewer 1, comment 7: We thank the reviewer for this helpful suggestion. Section 8 (Exosomal signaling) has been moved to the Future Perspectives section in the revised manuscript.

 

Reviewer 1, comment 8: The conclusions are not linked to the title.

 

Reply to reviewer 1, comment 8: We thank the reviewer for this constructive suggestion. The Conclusion section has been revised to more clearly reflect the central theme of the review, namely the inflammatory landscape of pregnancy and its role in linking maternal–fetal immune regulation with placental dysfunction and vascular disease. The revised text now explicitly connects immune dysregulation at the maternal–fetal interface with the development of placental-mediated complications and highlights the implications for future targeted therapeutic strategies.

 

Reviewer # 2.

Reviewer 2 comment 1: The review would benefit from deeper coverage of molecular mechanisms and immune cell interactions.

Reply to reviewer 2, comment 1: We thank the reviewer for this valuable suggestion. In response, the manuscript has been revised to further expand the discussion of molecular mechanisms and immune cell interactions at the maternal–fetal interface. Additional content has been incorporated addressing the roles of innate and adaptive immune populations, inflammasome signaling, cytokine networks, and angiogenic pathways, as well as their interactions with trophoblast biology and endothelial function. We incorporated a more detailed discussion of Th17 cells, B cells (including AT1-AA production), macrophage polarization, neutrophil participation, and their integration within the NLRP3 inflammasome cascade. In addition, we introduced a new subsection (Section 4.1) that addresses autophagy and its interactions with placental stress and inflammasome activation. These additions strengthen the mechanistic framework of the review and better integrate molecular and cellular insights into the pathophysiology of placental-mediated pregnancy disorders.

Modification in the manuscript: Relevant sections throughout the manuscript have been expanded to provide a more detailed discussion of immune cell dynamics and molecular inflammatory pathways involved in placental dysfunction.

Reviewer 2 comment 2: Figure 1 is small, incomplete, and unclear regarding immune interactions and marker expression.

Reply to reviewer 2, comment 2: Figure 1 has been substantially revised to improve both conceptual and visual representation. The updated figure now clearly delineates the maternal and fetal compartments, specifies the CD56^bright^CD16⁻ decidual NK phenotype, and illustrates key cytokine-mediated interactions among NK cells, macrophages, dendritic cells, and Tregs at the maternal-fetal interface. In addition, galectin signaling (Gal-1 and Gal-9) and relevant immune checkpoint interactions have been incorporated to better reflect current understanding of immunoregulatory mechanisms in placental biology. The overall graphical layout and color scheme were also refined to improve readability, structural balance, and interpretability of the immune interactions depicted. The graphic layout and color coding were improved to enhance clarity and balance.

Modification in the manuscript: Figure 1.

Reviewer 2 comment 3: Expand discussion of B cells, Th17 cells, dendritic cells, neutrophils, and MDSCs.

Reply to reviewer 2, comment 3: We thank the reviewer for this valuable suggestion. In the revised manuscript, we have expanded the discussion of additional immune cell populations at the maternal–fetal interface, including B cells, Th17 cells, dendritic cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), to provide a more comprehensive overview of the immune interactions contributing to placental inflammation and immune regulation.

Reviewer 2 comment 4: The role of galectins requires more detailed discussion and inclusion in figures.

Reply to reviewer 2, comment 4: We thank the reviewer for this important suggestion. In the revised manuscript, the figures have been updated, and the corresponding sections expanded to provide a more detailed discussion of this topic and its relevance to placental dysfunction and immune dysregulation at the maternal–fetal interface. Section 2.2 has been substantially expanded to include a detailed mechanistic discussion of Galectin-1 and Galectin-9, including glycan-mediated signaling, TIM-3 interactions, Treg modulation, and effects on spiral artery remodeling. Galectin dysregulation has also been incorporated into the redesigned Figure 1 and integrated into the updated final model (Figure 5), highlighting its contribution to immune tolerance and vascular adaptation.

Reviewer 2 comment 5: Improve Figure 2 (more informative and visual).

Reply to reviewer 2, comment 5: Figure 2 has been substantially redesigned to depict a molecular interaction network highlighting inflammasome activation and the reciprocal signaling among Th17 cells, macrophages, neutrophils, B cells, and regulatory T cells. The revised illustration emphasizes cytokine-driven amplification loops and immune cell crosstalk, thereby enhancing both the mechanistic coherence and visual clarity of the pathways implicated in inflammatory placental dysfunction.

Modification in the manuscript: Figure 2.

Reviewer 2 comment 6: Figure 5 lacks logical sequence and clear cause–effect relationships.

Reply to reviewer 2 comment 6: Figure 5 has been restructured into an integrated cascade model linking placental stress responses to key downstream molecular events, including NLRP3 inflammasome activation, dysregulation of galectin signaling, impaired autophagy, and angiogenic imbalance (sFlt-1, sEng, and PlGF), ultimately leading to maternal endothelial dysfunction. The revised figure now more clearly depicts the cause-and-effect relationships across these interconnected pathways, culminating in the clinical manifestations of preeclampsia and fetal growth restriction.

Modification in the manuscript: Figure 5.

Reviewer 2 comment 7: Add additional information on Galectin-9 and expand Treg discussion.

Reply to reviewer 2, comment 7: We thank the reviewer for this valuable suggestion. In the revised manuscript, we have expanded the discussion of Galectin-9 signaling via the TIM-3 pathway, highlighting its role in regulating NK cell activity and promoting regulatory T cell (Treg) expansion at the maternal–fetal interface. In addition, we incorporated a dedicated subsection on regulatory T cells, emphasizing their central role in maintaining immune tolerance and controlling inflammatory responses during pregnancy. The revised text further discusses how Treg dysfunction may contribute to endothelial injury, angiogenic imbalance, and the development of placental-mediated complications.

We hope these revisions adequately address your concerns. Please feel free to provide further guidance if you believe additional improvements are needed.

 

Once again, we appreciate your time and valuable input.

 

Sincerely,

 

 

Jezid Miranda, MD, PhD

Department of Obstetrics and Gynecology, Universidad de Cartagena

Cartagena de Indias, Colombia

Telephone: + 57 3014238444

jmirandaq@unicartagena.edu.co

Twitter: @JezidMiranda

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors, you addressed all my questions and in this for your manuscript is suitable for publication

Author Response

Second review:

Reviewer 1: "Dear authors, you addressed all my questions and in this for your manuscript is suitable for publication"

Reply to reviewer 1: Thank you very much for your time and for your thoughtful review. We truly appreciate your positive feedback and are glad that the revisions addressed your comments.

Reviewer 2 Report

Comments and Suggestions for Authors

Reviewer's Response to the Revised Version of the manuscript "Inflammation at the Maternal-Fetal Interface: Mechanisms Linking Maternal-Fetal Immunity to Preeclampsia and Fetal Growth Restriction"

 

I would like to note that the manuscript text and figures have been improved. However, when uploading the revised version of the manuscript, authors should highlight the changes made or indicate the line numbers where the changes were made. Otherwise, the re-review process becomes more complicated and time-consuming.

 

1. In their response to the reviewer, the authors wrote: “Reply to reviewer 2, comment 3: We thank the reviewer for this valuable suggestion. In the revised manuscript, we have expanded the discussion of additional immune cell populations at the maternal-fetal interface, including B cells, Th17 cells, dendritic cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), to provide a more comprehensive overview of the immune interactions contributing to placental inflammation and immune function. Regulation”.

However, the reviewer did not find any mention of MDSCs in the revised version of the manuscript. I believe these cells play an important role in maintaining tolerance during pregnancy, acting as regulators/suppressors of T-cell function. MDSCs have been studied in human pregnancy since 2007. During this time, the importance of these cells' functioning and the correlation between a decrease in their number and degree of activation and the development of miscarriage, preeclampsia, and other conditions have been demonstrated. Therefore, I believe MDSCs deserve a mention or a separate subsection.

Articles regarding MDSC during pregnancy (PMID): 24894988, 26712947, 26599285, 31703912, 34099889, 34509865.

Author Response

Comment 1: I would like to note that the manuscript text and figures have been improved. However, when uploading the revised version of the manuscript, authors should highlight the changes made or indicate the line numbers where the changes were made. Otherwise, the re-review process becomes more complicated and time-consuming.

Response 1:  Thank you for your helpful comment and for taking the time to review the revised manuscript. We did upload a version with the previous changes highlighted. For this resubmission, we have included the revisions within the same file to maintain clarity and consistency. We appreciate your understanding and thank you again for your time and consideration.

Comment 2: In their response to the reviewer, the authors wrote: “Reply to reviewer 2, comment 3: We thank the reviewer for this valuable suggestion. In the revised manuscript, we have expanded the discussion of additional immune cell populations at the maternal-fetal interface, including B cells, Th17 cells, dendritic cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), to provide a more comprehensive overview of the immune interactions contributing to placental inflammation and immune function. Regulation”.

However, the reviewer did not find any mention of MDSCs in the revised version of the manuscript. I believe these cells play an important role in maintaining tolerance during pregnancy, acting as regulators/suppressors of T-cell function. MDSCs have been studied in human pregnancy since 2007. During this time, the importance of these cells' functioning and the correlation between a decrease in their number and degree of activation and the development of miscarriage, preeclampsia, and other conditions have been demonstrated. Therefore, I believe MDSCs deserve a mention or a separate subsection.

Articles regarding MDSC during pregnancy (PMID): 24894988, 26712947, 26599285, 31703912, 34099889, 34509865.

Response 2: Thank you very much for your thoughtful comment and for sharing these relevant references. We have now included a new paragraph in the revised manuscript specifically addressing the role of MDSCs at the maternal–fetal interface, incorporating the suggested literature. We appreciate your valuable input, which has helped improve the manuscript.