Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis
Open accessAbstract
Objectives Literature suggests that neutrophils of patients with rheumatoid arthritis (RA) are primed to respond to N-formyl methionine group (formylated peptides). Animal models indicate that formylated peptides contribute to joint damage via neutrophil recruitment and inflammation in joints. Non-steroidal anti-inflammatory drugs are also known to inhibit formyl peptide-induced neutrophil activation. The predominant source of formylated peptides in sterile inflammatory conditions like RA is mitochondria, organelles with prokaryotic molecular signatures. However, there is no direct evidence of mitochondrial formyl peptides (mtNFPs) in the circulation of patients with RA and their potential role in neutrophil-mediated inflammation in RA, including their clinical significance.Methods Levels of mtNFPs (total fMet, MT-ND6) were analyzed using ELISA in plasma and serum obtained from patients in 3 cross-sectional RA cohorts (n = 275), a longitudinal inception cohort (n = 192) followed for a median of 8 years, and age/gender-matched healthy controls (total n = 134). Neutrophil activation assays were done in the absence or presence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H.Results Elevated levels of total fMet were observed in the circulation of patients with RA as compared to healthy controls (p < 0.0001) associating with disease activity and could distinguish patients with the active disease from patients with inactive disease or patients in remission. Baseline levels of total fMet correlated with current and future joint involvement, respectively and predicted the development of rheumatoid nodules (OR = 1.2, p = 0.04). Further, total fMet levels improved the prognostic ability of ACPA in predicting erosive disease (OR of 7.9, p = 0.001). Total fMet levels correlated with markers of inflammation and neutrophil activation. Circulating mtNFPs induced neutrophil activation in vitro through FPR1-dependent mechanisms.Conclusions Circulating mtNFPs could be novel biomarkers of disease monitoring and prognosis for RA and in investigating neutrophil-mediated inflammation in RA. We propose, FPR1 as a novel therapeutic target for RA.
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Mitochondrial fMet levels can distinguish RA patients by disease activity and are associated with current joint erosion and joint space narrowing at baseline.
“More importantly, mitochondrial fMet levels can distinguish patients based on disease activity and are associated with current joint erosion and joint space narrowing at baseline.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [185]
The Results report that total fMet levels distinguished RA patients by disease activity in cohorts RA1 and RA4. They also report correlations with current joint erosion and joint space narrowing in RA2, a follow-up cohort, but do not establish those associations at baseline. The paper discusses baseline fMet levels separately when assessing later outcomes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMitochondrial fMet levels are elevated in RA patients compared with healthy individuals and are associated with neutrophil-mediated inflammation and disease progression, including rheumatoid nodules.
“Mitochondrial fMet levels are elevated in patients with RA compared with healthy individuals and are associated with neutrophil-mediated inflammation and disease progression, including the development of rheumatoid nodules185.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [185]
Increased mitochondrial fMet peptides in three independent RA cohorts correlate with circulating neutrophil activation markers (NETs, calprotectin, peroxidase) and inflammation markers (CRP, ESR).
“Specifically, increased levels of mitochondrial fMet peptides, as has been observed in three independent cohorts of patients with RA, correlate with circulating levels of neutrophil activation markers, including levels of NETs, calprotectin and peroxidase, as well as with markers of inflammation (such as C-reactive protein (CRP) level and erythrocyte sedimentation rate).”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [185]
Mitochondrial fMet peptide-mediated signalling is a potential therapeutic target for neutrophil-dominant inflammation in sterile inflammatory conditions such as RA.
“Furthermore, mitochondrial fMet peptide-mediated signalling is a potential therapeutic target for ameliorating neutrophil-dominant inflammation in sterile inflammatory conditions such as RA185.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [185]
Mitochondrial fMet peptides in RA plasma can support neutrophil activation in vitro via FPR1.
“Notably, mitochondrial fMet peptides circulating in the plasma of patients with RA can support neutrophil activation in vitro via FPR1 (as shown by FPR1 blockade experiments)185.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [185]
Baseline mitochondrial fMet levels predict development of extra-articular nodules.
“Furthermore, the mitochondrial fMet levels at baseline are predictive of extra-articular nodules development.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [185]
Mitochondrial fMet peptides might be useful novel clinical biomarkers for disease activity and severity.
“Overall, these findings suggest that mitochondrial fMet peptides might be useful novel clinical biomarkers for measuring disease activity and disease severity.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [185]
Adding mitochondrial fMet measurements improves the prognostic capacity of ACPA positivity to predict erosive disease in RA.
“Incorporating measurements of mitochondrial fMet level can improve the prognostic capacity of ACPA positivity to predict erosive disease in RA.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [185]
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References 52 · Cited by 58
- Authors
- Duvvuri, B., Baddour, A. A., Deane, K. D., Feser, M. L., Nelson, J. L., Demoruelle, M. K., & Lood, C.
- Affiliations
- University of Washington (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Lood, Christian
- ORCID
- Venue
- Journal of Autoimmunity
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 119
- Pages
- 102630
- ISSN
- 0896-8411 (ISSN-L)
- PMC
- PMC8062236
- OpenAlex
- W3139010036
- Cited by
- 58
- References
- 52
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 13 · 2023: 7 · 2022: 21
- FWCI
- 7.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Autoimmunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Center for Advancing Translational Sciences
- NIH
- Arthritis National Research Foundation
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- rheumatoid arthritis, formyl peptides, neutrophil activation, FPR1, disease activity markers, rheumatoid nodules, anti-citrullinated protein antibodies, erosive disease, joint involvement, neutrophilic inflammation, therapeutic target
- MeSH terms
- Adolescent, Adult, Aged, Arthritis, Rheumatoid, Disease Susceptibility, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Mitochondria, Neutrophils, Peptides, Prognosis, Severity of Illness Index, Biomarkers, Case-Control Studies, Reactive Oxygen Species, Neutrophil Activation, Disease Progression, Young Adult, Transcriptome
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