Elevated LL-37/FPR2 Axis and its Regulatory Role for Gingival Fibroblasts in Periodontitis

INTRODUCTION AND AIMS: LL-37, an antimicrobial peptide with dual pro-/anti-inflammatory roles, has been implicated in the pathogenesis of periodontitis, yet its specific action through its receptor Formyl peptide receptor 2 (FPR2) remains unclear. This study aimed to elucidate the expression profile of the LL-37/FPR2 axis in periodontitis and its regulatory effects on gingival fibroblasts (GFs). METHODS: Fifty-seven periodontitis patients and fifty-seven healthy controls were included to assess the levels of LL-37 and FPR2 in gingival tissues, gingival crevicular fluid and GFs, as well as to assess their correlation with disease progression. Primary human GFs were isolated and subsequently stimulated with Porphyromonas gingivalis lipopolysaccharide alongside varying concentrations of LL-37. To elucidate the functional role of FPR2 in this system, targeted gene silencing was performed using small interfering RNA. RESULTS: Both LL-37 and FPR2 were upregulated in gingival tissues or gingival crevicular fluid from periodontitis patients, showing a significant positive correlation. FPR2 expression increased in GFs under periodontal inflammatory conditions, and high concentration of LL-37 exacerbated pro-inflammatory response in GFs via FPR2. Clinically, elevated LL-37 and FPR2 correlated with disease severity, particularly in patients with higher LL-37 expression. Patients with co-upregulation of both LL-37 and FPR2 exhibited more severe periodontitis. CONCLUSIONS: The LL-37/FPR2 axis was co-upregulated in periodontitis-affected gingival tissues and correlated with disease severity. The LL-37/FPR2 axis exacerbated pro-inflammatory response in GFs under periodontal inflammatory conditions, suggesting its potential as a therapeutic target for mitigating periodontal inflammation. CLINICAL RELEVANCE: We found that the co-upregulation of LL-37/FPR2 in periodontitis-affected gingival tissues, positively correlates with clinical parameters (PD/CAL). These findings provide new insights into the dual role of LL-37 in periodontal inflammation and suggest novel strategies for targeted therapy by selectively inhibiting high-concentration LL-37/FPR2 signaling.