Abstract
The eye is highly susceptible to inflammation-induced tissue damage; however, the mechanisms that drive inflammation resolution during ocular infections remain unclear. In this study, we utilize a murine model of intraocular bacterial infection (S. aureus-induced endophthalmitis) and lipidomics analysis to uncover a critical role of pro-resolving lipid mediators, particularly resolvin D1 (RvD1), in resolving inflammation and restoring ocular tissue homeostasis and vision. RvD1 protects mouse eyes from severe endophthalmitis by enhancing bacterial clearance, suppressing intraocular inflammation, and preserving retinal structure and function. Pharmacological inhibition of formyl peptide receptor 2 (FPR2) reveals that RvD1’s protective effects mainly rely on FPR2 signaling. Unexpectedly, RvD1 is unable to resolve inflammation or protect the eye in the absence of Toll-like receptor 2 (TLR2), a critical pattern recognition receptor in ocular S. aureus infections. These findings reveal an unrecognized interplay between TLR2 and FPR2 signaling, including their mutual regulation and physical receptor interactions during bacterial infection. Overall, these findings provide new insights into the coordinated roles of TLR2 and FPR2 in resolving inflammation and protecting the eye during bacterial infections.
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All relevant data are included in the manuscript figures, supplementary information, and raw data points as supplementary files. Uncropped western blot images and the source data underlying all figures are provided as Supplementary Information. The source data behind the graphs are provided in supplementary data 1-11.
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Acknowledgements
This study is supported in part by the National Institute of Health (NIH)/National Eye Institutes (NEI) grants R01EY026964, R01EY027381, R01EY035499, and R21EY037082 to A.K. (Ashok Kumar) and R01EY032495 to P.K.S. This research is also supported in part by an unrestricted grant to the Kresge Eye Institute/Department of Ophthalmology, Visual, and Anatomical Sciences from Research to Prevent Blindness Inc. The immunology resource core is supported by an NIH Center grant P30EY004068. The funders had no role in the study design, data collection, interpretation, or decision to submit the work for publication. We thank Charles N. Serhan, PhD, DSc (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA), for his insightful discussions and expert guidance on bioactive lipid mediators.
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P.K.S. (Pawan Kumar Singh) conceived, designed, and performed the experiments, analyzed the data, and wrote the paper. S.S. (Sukhvinder Singh) and Aj.K. (Ajay Kumar) planned and performed the experiment, helped with the data analysis, graph preparation, and editing of the manuscript. S.G. (Shailendra Giri) provided intellectual input and edited the manuscript. A.K. (Ashok Kumar) conceived the idea and project administration, helped with the research planning, provided funding, and edited the manuscript. All the authors read and approved the final version of the manuscript.
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Singh, P.K., Singh, S., Kumar, A. et al. Resolvin D1 requires TLR2-FPR2 crosstalk for inflammation resolution and protection during ocular bacterial infection. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09840-3
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DOI: https://doi.org/10.1038/s42003-026-09840-3
