Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis

Duvvuri, Bhargavi; Baddour, Al Anoud; Deane, Kevin D.; Feser, Marie L.; Nelson, J. Lee; Demoruelle, M. Kristen; Lood, Christian

doi:10.1016/j.jaut.2021.102630

Cited by 28 publications

(23 citation statements)

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“…Association between mitochondrial proteins and neutrophil activation was shown in our recent study of RA patients (28). Similarly, we found levels of fMet associating with neutrophil activation markers like calprotectin and NETs in SSc patients, supporting the hypothesis of fMet-mediated neutrophil activation.…”

Section: Discussionsupporting

confidence: 89%

“…To investigate whether the capacity of plasma to induce neutrophil activation was dependent on fMet, neutrophils were pre-incubated with the specific fMet receptor FPR1 antagonist Cyclosporine H (CsH) prior to addition of plasma samples. We and others have previously shown the specificity of CsH as an FPR1 inhibitor ( 28 , 37 ). For patients with high levels of fMet, plasma-mediated neutrophil activation was reduced in the presence of the FPR1 inhibitor (CD66b; p<0.01 and CD11b; p<0.0001).…”

Section: Resultsmentioning

confidence: 88%

“…We have recently demonstrated that patients with RA have elevated plasma levels of mitochondrial-derived N-formyl methionine peptides (fMet), a potent neutrophil agonist promoting neutrophil chemotaxis and activation, including NET formation ( 28 ). However, whether patients with SSc have elevated levels of fMet, and their potential contribution to neutrophil-mediated inflammation is not known.…”

Section: Resultsmentioning

confidence: 99%

“…These microparticles resulted in neutrophil activation and generation of NETs and were further ablated in presence of BoxA, a competitive inhibitor of HMGB1, indicating a platelet-microparticle specific neutrophil activation via HMGB1 ( 22 ). Although not in the context of SSc, our group has recently demonstrated extracellular mitochondrial N-formyl methionine (fMet) peptides abundantly present in RA patients ( 28 ) as well as in systemic vasculitides (Michailidou et al., under revision) suggesting fMet-mediated neutrophil activation possibly being a central process in several autoimmune inflammatory conditions. Whether SSc patients have elevated levels of extracellular mitochondrial fMet and their role in neutrophil-mediated inflammation has so far not been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…During inflammation, neutrophils are activated by various molecules, including cytokines, immune complexes (ICs) and damage-associated molecular patterns (DAMPs) generated by mitochondrial components (11,24,25). We and others have reported mitochondrial extrusion and presence of extracellular mitochondrial components in several autoimmune disorders such as SLE and RA (26)(27)(28). Given their prokaryotic origin, mitochondria contain several proinflammatory components that can engage neutrophils.…”

Section: Introductionmentioning

confidence: 99%

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N-Formyl Methionine Peptide-Mediated Neutrophil Activation in Systemic Sclerosis

et al. 2022

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Exaggerated neutrophil activation and formation of neutrophil extracellular traps (NETs) are reported in systemic sclerosis (SSc) but its involvement in SSc pathogenesis is not clear. In the present study we assessed markers of neutrophil activation and NET formation in SSc patients in relation to markers of inflammation and disease phenotype. Factors promoting neutrophil activation in SSc remain largely unknown. Among the neutrophil activating factors, mitochondrial-derived N-formyl methionine (fMet) has been reported in several autoinflammatory conditions. The aim of the current study is to assess whether SSc patients have elevated levels of fMet and the role of fMet in neutrophil-mediated inflammation on SSc pathogenesis. Markers of neutrophil activation (calprotectin, NETs) and levels of fMet were analyzed in plasma from two SSc cohorts (n=80 and n=20, respectively) using ELISA. Neutrophil activation assays were performed in presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporin H. Elevated levels of calprotectin and NETs were observed in SSc patients as compared to healthy controls (p<0.0001) associating with SSc clinical disease characteristics. Further, SSc patients had elevated levels of circulating fMet as compared to healthy controls (p<0.0001). Consistent with a role for fMet-mediated neutrophil activation, fMet levels correlated with levels of calprotectin and NETs (r=0.34, p=0.002; r=0.29, p<0.01 respectively). Additionally, plasma samples from SSc patients with high levels of fMet induced de novo neutrophil activation through FPR1-dependent mechanisms. Our data for the first time implicates an important role for the mitochondrial component fMet in promoting neutrophil-mediated inflammation in SSc.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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N-Formyl Methionine Peptide-Mediated Neutrophil Activation in Systemic Sclerosis

et al. 2022

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Prediction of Erosive Disease Development by Antimitochondrial Antibodies in Rheumatoid Arthritis

Moore

Wang

Duvvuri

et al. 2023

Arthritis & Rheumatology

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Objective Mitochondria are found in the extracellular space in rheumatoid arthritis (RA). However, whether mitochondria are a source of autoantigens in RA has not been carefully addressed. Thus, we undertook this study to investigate the presence and significance of antimitochondrial antibodies (AMAs) in patients with RA. Methods AMAs were measured in serum samples from 3 cross‐sectional cohorts of RA patients (n = 95, n = 192, and n = 117) and healthy individuals (n = 38, n = 72, and n = 50) using a flow cytometry–based assay. Further, AMAs were detected using an anti–mitofusin‐1 (anti–MFN‐1) IgG enzyme‐linked immunosorbent assay and Western blot analysis. A longitudinal inception cohort, followed up for a median of 8 years, was used to study disease progression. Results AMA levels were elevated in RA patients from all 3 cohorts as compared to healthy individuals (P < 0.001, P < 0.05, and P < 0.01), with a range of 14–26% positivity. Levels of anti–MFN‐1 antibodies correlated with AMA levels (r = 0.31, P = 0.006) and were elevated in RA patients as compared to healthy individuals (P < 0.001). The presence of AMAs was associated with erosive disease (P < 0.05) and interstitial lung disease (P < 0.01). Further, AMA levels were found to predict erosive disease (odds ratio [OR] 4.59, P = 0.006) and joint space narrowing (OR 3.08, P = 0.02) independent of anti–citrullinated protein antibodies. Finally, anti–MFN‐1 antibodies identified seronegative patients developing erosive disease (OR 9.33; P = 0.02). Conclusion Our findings demonstrate the presence of novel autoantibodies targeting mitochondria in the setting of RA. AMAs were used to stratify patients based on disease phenotype and to predict development of erosive disease, including in patients with seronegative disease. Our results highlight the essential role of mitochondria in the pathogenesis of RA and suggest a possible benefit of therapies targeting mitochondrial‐mediated inflammation and clearance in these patients.

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Mitophagy in relation to chronic inflammation/ROS in aging

Kong,

Li,

et al. 2024

Mol Cell Biochem

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Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis

Cited by 28 publications

References 50 publications

N-Formyl Methionine Peptide-Mediated Neutrophil Activation in Systemic Sclerosis

N-Formyl Methionine Peptide-Mediated Neutrophil Activation in Systemic Sclerosis

Prediction of Erosive Disease Development by Antimitochondrial Antibodies in Rheumatoid Arthritis

Mitophagy in relation to chronic inflammation/ROS in aging

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