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Published on: January 7, 2019
N-formyl methionine peptide-driven neutrophil activation in idiopathic inflammatory myopathies
Jorge A Gonzalez-Chapa1, Begum Horuluoglu2,3, Antonella Notarnicola2,3,4
1Division of Rheumatology, University of Washington, Seattle, WA, USA.
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.
Insights
N-formyl methionine (fMET) activates neutrophils via formyl peptide receptor 1 (FPR1) in inflammatory myopathies like dermatomyositis and inclusion body myositis. Targeting this fMET-FPR1 pathway may offer new treatments for idiopathic inflammatory myopathies (IIMs).
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Neutrophil activation is elevated in inflammatory myopathies and linked to disease activity.
- The precise mechanisms driving neutrophil activation in idiopathic inflammatory myopathies (IIMs) are not fully understood.
Purpose of the Study:
- To investigate the role of N-formyl methionine (fMET) in formyl peptide receptor 1 (FPR1)-mediated neutrophil activation in dermatomyositis (DM) and inclusion body myositis (IBM).
Main Methods:
- Plasma samples from IBM, DM, and healthy controls were analyzed for fMET, calprotectin, and neutrophil elastase DNA (NE-DNA) using ELISA.
- Neutrophil activation markers (CD11b, CD66b) were assessed via flow cytometry after plasma stimulation, with and without FPR1 inhibition.
- Correlations between fMET levels, muscle strength (MMT8), and neutrophil activation markers were examined.
Main Results:
- Patients with DM and IBM exhibited significantly higher plasma fMET levels compared to healthy controls.
- Elevated NE-DNA complexes were observed in both DM and IBM patients.
- FPR1 inhibition markedly reduced plasma-induced neutrophil activation in DM and IBM, suggesting fMET-FPR1 signaling is crucial.
Conclusions:
- fMET-FPR1 signaling is a key driver of neutrophil activation in DM and IBM, contributing to inflammation and muscle damage.
- Inhibition of the fMET-FPR1 pathway presents a potential therapeutic strategy for IIMs.
