Resolvin D1 requires TLR2-FPR2 crosstalk for inflammation resolution and protection during ocular bacterial infection

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.