ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
This article is part of the Research TopicInflammation as a fundamental mechanism of strokeView all 6 articles
S100A8/A9 Inhibition Reduces Splenic Myelopoiesis and Improves Outcomes After Stroke
Provisionally accepted
Hyun Ah Kim1*
Annas Al-sharea2
Hannah X. Chu1
Sung-chun Tang3
Samoda A. Rupasinghe1
Shenpeng Zhang1Prabhakara N Nagareddy4
Grant Drummond1
Thiruma Valavan Arumugam1Andrew J. Murphy2
Christopher G Sobey1*
Man Lee2- 1La Trobe University, Melbourne, Australia
- 2Baker Heart and Diabetes Institute, Melbourne, Australia
- 3National Taiwan University Hospital, Taipei City, Taiwan
- 4The University of Oklahoma Health Sciences, Oklahoma City, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Introduction: Neutrophils are among the earliest immune cells to infiltrate the ischemic brain and contribute to secondary neuronal damage. The alarmin S100 calcium-binding protein A8/A9 (S100A8/A9), predominantly released by neutrophils, is upregulated during this process. Although the bone marrow is recognised as the principal site of neutrophil production via myelopoiesis, the role of the spleen as an immune-responsive organ remains incompletely understood. Methods: In this study, we employed a transient middle cerebral artery occlusion (MCAO) model in male C57Bl/6 mice and examined immune responses 24 hours post-stroke in the blood, bone marrow and spleen using flow cytometry. To understand the role of S100A8/A9 in modulating stroke-induced myelopoiesis, we administered a small molecule inhibitor of S100A8/A9, ABR-215757, before and after stroke. Results: Analysis of human brain tissue (4 stroke patients, 2 controls) indicated the presence of neutrophils and S100A8/A9 in infarcted regions. Interestingly, we observed a marked increase in splenic neutrophils, accompanied by an expansion of myeloid progenitors, indicating activation of extramedullary myelopoiesis. Given our previous work showing that S100A8/A9 promotes myelopoiesis, we pharmacologically inhibited S100A8/A9 to determine if this would modulate stroke-induced myelopoiesis. Treatment with ABR-215757 at 24 hours post-stroke led to reduced splenic myelopoiesis, reversed neutrophilia, enhanced forelimb grip strength, and a caused a one-third reduction in infarct size. Conclusion: These findings identify the spleen as a key contributor to neutrophil production following stroke and suggest that targeting S100A8/A9 may mitigate myeloid skewing and improve neurological recovery.
Keywords: ABR-215757, Inflammation, middle cerebral artery occlusion, Myelopoiesis, S100A8/A9, Stroke
Received: 16 Dec 2025; Accepted: 22 Jan 2026.
Copyright: © 2026 Kim, Al-sharea, Chu, Tang, Rupasinghe, Zhang, Nagareddy, Drummond, Arumugam, Murphy, Sobey and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Hyun Ah Kim
Christopher G Sobey
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.