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Home / Equine Research Bank / Int J Mol Sci / Activation of the S100A8/A9 Alarmin Amplifies Inflammatory P...
International journal of molecular sciences2026; 27(3); 1550; doi: 10.3390/ijms27031550

Activation of the S100A8/A9 Alarmin Amplifies Inflammatory Pathways in Equine Ascending Placentitis.

Abstract: Ascending placentitis is a significant cause of equine pregnancy loss, yet the upstream inflammatory triggers are poorly defined. Recently, we identified S100A8/S100A9 (S100A8/A9) alarmins as potential upstream regulators in a chronic equine placentitis model. The current study aimed to determine whether this upregulation is sustained in the acute model and in clinical cases, and to elucidate the expression of their downstream inflammatory mediators. Using an experimental model, we quantified mRNA expression in acute ( = 5) and chronic ( = 6) placentitis induced by ssp. . We found mRNA expression of and was significantly upregulated in chorioallantois during both acute ( < 0.001) and chronic ( < 0.0001) disease compared to controls ( = 5), demonstrating their role is not limited to chronic pathology. A strong positive correlation ( = 0.945) underscored their coordinated expression. Immunohistochemistry revealed minimal staining in controls but dense infiltrations of S100A8/A9-positive neutrophils and macrophages in placentitis tissues. To define the clinical relevance of the downstream pathway, we analyzed RNA sequencing data from clinical placentitis cases (placentitis, = 4) compared to normal postpartum placenta (control, = 4). This confirmed upregulation of and revealed a concurrent increase in their receptors (, ) and a spectrum of NF-κB-driven effectors, including pro-inflammatory cytokines (, , ), chemokines (, , ), and the apoptotic mediator . Our findings establish that S100A8/A9 upregulation is a sustained feature of equine placentitis and delineates a coherent S100A8/A9-TLR4/RAGE-NF-κB signaling axis that drives inflammation and tissue damage in clinical disease. These findings highlight the diagnostic potential of S100A8/A9 and position this alarmin system as a promising therapeutic target for mitigating infection-induced pregnancy loss.
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Publication Date: 2026-02-04 PubMed ID: 41683969PubMed Central: PMC12897833DOI: 10.3390/ijms27031550Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • The study explores the role of the S100A8/A9 protein complex (alarmins) in triggering and amplifying inflammation in equine ascending placentitis, a major cause of pregnancy loss in horses.
  • The research demonstrates that S100A8/A9 is upregulated in both acute and chronic forms of placentitis and identifies downstream inflammatory pathways activated by these alarmins, suggesting potential diagnostic and therapeutic implications.

Background and Purpose

  • Equine ascending placentitis: A serious infectious disease causing inflammation of the placenta, leading to pregnancy loss in horses.
  • Knowledge gap: The early molecular triggers and inflammatory mechanisms driving the disease are not well understood.
  • S100A8/A9 alarmins: Known damage-associated molecular pattern (DAMP) proteins that can activate immune responses and inflammation; previously implicated in chronic equine placentitis.
  • Objective: To determine if S100A8/A9 upregulation also occurs in acute placentitis, and to investigate the downstream inflammatory signaling pathways activated by these proteins in both experimental and clinical cases.

Methods

  • Experimental model: Induced placentitis in horses using bacterial infection (Streptococcus equi ssp.), with groups for acute placentitis (n=5), chronic placentitis (n=6), and healthy controls (n=5).
  • Gene expression analysis: Measured mRNA levels of S100A8 and S100A9 in placental tissues using quantitative techniques to assess their expression during acute and chronic disease.
  • Immunohistochemistry: Localized S100A8/A9 proteins in tissue sections to identify cell types involved and intensity of inflammatory infiltration.
  • RNA sequencing data: Analyzed samples from naturally occurring (clinical) placentitis cases (n=4) versus normal postpartum placentas (n=4) to identify broader changes in inflammatory mediator expression downstream of S100A8/A9.

Key Findings

  • S100A8/A9 mRNA upregulation: Significantly increased expression in the chorioallantois tissue during both acute (p<0.001) and chronic (p<0.0001) placentitis compared to controls.
  • Coordinated expression: High positive correlation (r=0.945) between S100A8 and S100A9, indicating that these alarmins are co-regulated during placental inflammation.
  • Cellular localization: Immunohistochemistry showed minimal staining in healthy placentas, but dense infiltration of neutrophils and macrophages positive for S100A8/A9 in diseased tissue, highlighting their immune cell source.
  • Downstream inflammatory pathways: RNA-seq data from clinical cases revealed not only upregulation of S100A8/A9 but also increased expression of their receptors TLR4 and RAGE.
  • Activated signaling axis: Evidence of activation of the NF-κB pathway, a key transcription factor controlling inflammation.
  • Elevated inflammatory mediators: Increased levels of pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α), chemokines (e.g., CCL2, CXCL8, CXCL10), and apoptotic mediator expression, supporting the role of S100A8/A9 in driving inflammation and tissue damage.

Conclusions and Implications

  • S100A8/A9 are not only involved in chronic equine placentitis but also play a sustained and active role in acute inflammatory responses, amplifying disease severity.
  • The study outlines a clear mechanistic pathway: S100A8/A9 alarmins bind to innate immune receptors (TLR4 and RAGE), triggering NF-κB activation and release of various inflammatory mediators that contribute to placental inflammation and damage.
  • This signaling axis may serve as a biomarker for diagnosing placentitis due to its consistent upregulation in clinical cases.
  • Targeting the S100A8/A9-TLR4/RAGE-NF-κB pathway offers a promising therapeutic strategy to reduce inflammation-induced pregnancy loss in horses.
  • Further research could explore inhibitors or modulators of these alarmins or their downstream pathways for clinical interventions.

Cite This Article

APA
Scoggin KE, Rakha SI, Abdellatif AM, Adlan F, Helmy YA, Ruby R, Ball B, Boakari Y, Ali HE. (2026). Activation of the S100A8/A9 Alarmin Amplifies Inflammatory Pathways in Equine Ascending Placentitis. Int J Mol Sci, 27(3), 1550. https://doi.org/10.3390/ijms27031550

Publication

International journal of molecular sciences
ISSN: 1422-0067
NlmUniqueID: 101092791
Country: Switzerland
Language: English
Volume: 27
Issue: 3
PII: 1550

Researcher Affiliations

Scoggin, Kirsten E
  • Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA.
Rakha, Shimaa I
  • Department of Theriogenology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt.
Abdellatif, Ahmed M
  • Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt.
Adlan, Fatma
  • Department of Theriogenology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt.
Helmy, Yosra A
  • Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA.
Ruby, Rebecca
  • Veterinary Diagnostic Laboratory, University of Kentucky, Lexington, KY 40511, USA.
Ball, Barry
  • Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA.
Boakari, Yatta
  • Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A & M University, College Station, TX 77843, USA.
Ali, Hossam El-Sheikh
  • Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA.

MeSH Terms

  • Animals
  • Pregnancy
  • Calgranulin A / metabolism
  • Calgranulin A / genetics
  • Female
  • Calgranulin B / metabolism
  • Calgranulin B / genetics
  • Horses
  • Alarmins / metabolism
  • Alarmins / genetics
  • Horse Diseases / metabolism
  • Horse Diseases / microbiology
  • Horse Diseases / genetics
  • Horse Diseases / pathology
  • Inflammation / metabolism
  • Placenta Diseases / metabolism
  • Placenta Diseases / veterinary
  • Placenta Diseases / microbiology
  • Placenta Diseases / genetics
  • Placenta Diseases / pathology
  • Streptococcus equi
  • Streptococcal Infections / veterinary
  • Streptococcal Infections / metabolism
  • Streptococcal Infections / microbiology
  • Placenta / metabolism
  • Placenta / pathology
  • Placenta / microbiology
  • Signal Transduction

Grant Funding

  • N/A / Gluck Equine Research Foundation
  • N/A / 2024 Equine Research Award - Boehringer Ingelheim
  • HATCH #7009671 / USDA Capacity Project

Conflict of Interest Statement

The authors declare no conflicts of interest.

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