Macrophage sub-populations and the lipoxin A4 receptor implicate active inflammation during equine tendon repair.
Authors: Dakin Stephanie Georgina, Werling Dirk, Hibbert Andrew, Abayasekara Dilkush Robert Ephrem, Young Natalie Jayne, Smith Roger Kenneth Whealands, Dudhia Jayesh
Journal: PloS one
Summary
# Editorial Summary: Macrophage Populations and Inflammation Resolution in Equine Tendon Injury This research examined how different macrophage subsets and inflammation-resolving pathways function during equine superficial digital flexor tendon healing, using postmortem tissue samples from uninjured tendons alongside naturally injured tendons in both acute (3–6 weeks) and chronic (>3 months) phases. The investigators identified distinct macrophage populations based on surface markers (CD14, CD206) and tracked expression of the lipoxin A₄ receptor (FPR2/ALX), which signals resolution of inflammation. Pro-inflammatory M1 macrophages dominated the acute injury phase, then shifted toward anti-inflammatory M2 populations in chronic injury; however, expression of the FPR2/ALX receptor—which should help terminate inflammation—remained low in chronic cases despite elevated Annexin A1 (the ligand that activates this pathway), suggesting a failure to resolve inflammation properly. Laboratory testing confirmed that tendon cells can produce lipoxin A₄ and upregulate FPR2/ALX when exposed to inflammatory triggers like IL-1β, yet this protective response appears insufficient in duration and magnitude during natural injury, potentially allowing chronic inflammation and maladaptive fibrotic repair to persist. For practitioners managing tendon injuries, these findings indicate that the tissues' own inflammation-resolving mechanisms may be inadequate, which has implications for recovery expectations, timing of rehabilitation protocols, and potential therapeutic targets—such as interventions aimed at enhancing lipoxin A₄ signalling or optimising macrophage phenotype transitions—to move injured tendons more decisively toward resolution and functional repair rather than chronic fibrosis.
Read the full abstract on PubMed
Practical Takeaways
- •Early intervention during the sub-acute phase (3-6 weeks post-injury) may be critical to prevent transition to chronic inflammation, as the inflammatory environment shifts from M1 to M2 dominance over time
- •Chronic tendon injuries show evidence of incomplete inflammation resolution despite the presence of repair-associated M2 macrophages, suggesting that standard healing timelines may be insufficient and additional therapeutic support may be needed
- •Understanding macrophage polarization during tendon healing could inform development of targeted therapies to enhance resolution of inflammation and prevent fibrotic repair complications
Key Findings
- •M1 macrophages (pro-inflammatory) predominated in sub-acute tendon injury (3-6 weeks post-injury), while M2 macrophages (anti-inflammatory) became dominant in chronic injury (>3 months)
- •FPR2/ALX expression was significantly upregulated in sub-acute injury but not in chronic injury, suggesting incomplete inflammation resolution
- •Tenocytes produced lipoxin A4 and upregulated FPR2/ALX expression in response to pro-inflammatory stimuli (IL-1β and PGE2) in vitro, indicating a protective mechanism
- •Persistence of M2 macrophages combined with reduced FPR2/ALX expression in chronic injury suggests a mechanism for incomplete inflammation resolution and fibrotic repair