N-formyl methionine peptide-driven neutrophil activation in idiopathic inflammatory myopathies.

OBJECTIVE

Neutrophil activation is heightened in inflammatory myopathies and associated with disease activity, yet its mechanisms remain unclear. This study explores the role of N-formyl methionine (fMET) in formyl peptide receptor 1 (FPR1)-mediated neutrophil activation in idiopathic inflammatory myopathies (IIMs), focusing on dermatomyositis (DM) and inclusion body myositis (IBM).

METHODS

Plasma from IBM (n = 46), DM (n = 40) and healthy controls (n = 40) was analysed for fMET, calprotectin, neutrophil elastase DNA (NE-DNA) and cytokines using ELISA. Neutrophil markers CD11b and CD66b were assessed by flow cytometry following plasma stimulation with or without FPR1 inhibition. Correlation analyses were performed between fMET, muscle strength (MMT8) and neutrophil activation markers.

RESULTS

DM and IBM patients had significantly higher plasma fMET levels than controls (P < 0.0001 for DM; P = 0.0002 for IBM). Median fMET levels were 13 719 pg/ml (75th percentile: 17 236 pg/ml) for IBM, 14 780 pg/ml (75th percentile: 17 631 pg/ml) for DM and 8449 pg/ml (75th percentile: 12 632 pg/ml) for controls. fMET correlated inversely with MMT8 in antibody-negative IBM (r = -0.53, P = 0.02). Calprotectin was elevated in DM (P = 0.01) but not IBM; NE-DNA complexes were increased in both DM (P = 0.03) and IBM (P < 0.0001). FPR1 inhibition significantly reduced plasma-induced neutrophil activation in DM (P < 0.0001) and IBM (P = 0.0012), restoring CD66b and partially CD11b to control levels.

CONCLUSION

Our findings show that fMET-FPR1 signalling drives neutrophil activation in DM and IBM, promoting inflammation and muscle damage. Targeting this pathway may offer a novel IIM therapy.