Background/Purpose: Systemic sclerosis (SSc) is a complex systemic autoimmune disease, and its etiology is unknown. Exaggerated neutrophil activation and formation of neutrophil extracellular traps (NETs) are reported in SSc, but its involvement in SSc pathogenesis is not clear. In the present study we assessed markers of neutrophil activation and NET formation in plasma samples from SSc patients (n=101), investigating their association with markers of inflammation and disease phenotype in SSc. Additionally, factors contributing to neutrophil-mediated inflammation in SSc remains largely unknown. Among the neutrophil activating factors, extracellular mitochondrial components have been reported in several autoinflammatory conditions, supporting inflammation and recruitment of neutrophils through among others mitochondrial-derived N-formyl methionine (fMet). The aim of the current study is to assess whether SSc patients have elevated levels of extracellular mitochondrial components and their role in neutrophil-mediated inflammation in SSc pathogenesis.

Methods: Markers of neutrophil activation (calprotectin), cell death (NETs, measured as myeloperoxidase-DNA complexes) and levels of fMet were analyzed in plasma obtained from two SSc patient cohorts (Cohort I: 81 SSc and 40 healthy controls, Cohort II: 20 SSc and 24 healthy controls) using ELISA. Neutrophil activation assays were performed in presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporin H.

Results: Elevated levels of neutrophil activation markers, calprotectin and NETs were observed in SSc patients as compared to healthy controls (P < 0.0001) associating with a severe disease phenotype. Further, SSc patients had elevated levels of fMet in circulation as compared to healthy controls (P < 0.0001). Of note, levels of fMet were significantly higher in patients with diffuse versus limited SSc patients (p< 0.04). Consistent with a role for fMet in promoting neutrophil activation, fMet levels correlated with neutrophil activation markers calprotectin and NETs (r=0.34, p=0.002; r=0.29, p< 0.01 respectively). Additionally, plasma samples from a subset of SSc patients with high levels of fMet in circulation induced de novo neutrophil activation through FPR1-dependent mechanisms.

Conclusion: Our data for the first time implicates an important role for the mitochondrial component fMet in promoting neutrophil-mediated inflammation in SSc. We propose, targeting fMet-mediated inflammation pathways may provide opportunities to treat SSc patients, which is in need of novel therapeutics. Finally, our neutrophil and mitochondrial-derived biomarkers may provide for opportunities to better stratify patients and in patient management.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/n-formyl-methionine-peptide-mediated-neutrophil-activation-in-systemic-sclerosis/