Molecular Determinants of Neutrophil Extracellular Vesicles That Drive Cartilage Regeneration in Inflammatory Arthritis

Bethan L. Thomas; Trinidad Montero-Melendez; Silvia Oggero; Magdalena K. Kaneva; David Chambers; Andreia L. Pinto; Alessandra Nerviani; Davide Lucchesi; Shani Austin-Williams; Mohammed T. Hussain; Costantino Pitzalis; Benjamin Allen; Marzia Malcangio; Francesco Dell'Accio; Lucy V. Norling; Mauro Perretti

doi:10.1002/art.42958

Molecular Determinants of Neutrophil Extracellular Vesicles That Drive Cartilage Regeneration in Inflammatory Arthritis

Bethan L. Thomas, Trinidad Montero-Melendez, Silvia Oggero, Magdalena K. Kaneva, David Chambers, Andreia L. Pinto, Alessandra Nerviani, Davide Lucchesi, Shani Austin-Williams, Mohammed T. Hussain, Costantino Pitzalis, Benjamin Allen, Marzia Malcangio, Francesco Dell'Accio, Lucy V. Norling^*, Mauro Perretti^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Objective: This study was undertaken to establish the potential therapeutic profile of neutrophil-derived extracellular vesicles (EVs) in experimental inflammatory arthritis and associate pharmacological activity with specific EV components, focusing on microRNAs. Methods: Neutrophil EVs were administered intra-articularly through a prophylactic or therapeutic protocol to male C57BL/6 mice undergoing serum-transfer–induced inflammatory arthritis. Transcriptomic analysis of knees was performed on joints following EV administration, naive and arthritic mice (untreated; n = 4/group) and EV-treated diseased mice (intra-articular administration) with contralateral (vehicle-treated; n = 8/group). Comparison of healthy donor and patients with rheumatoid arthritis (RA) neutrophil EVs was performed. Results: EVs afforded cartilage protection with an increase in collagen-II and reduced collagen-X expression within the joint. To gain mechanistic insights, RNA sequencing of the arthritic joints was conducted. A total of 5,231 genes were differentially expressed (P < 0.05), with 257 unique to EV treatment. EVs affected key regenerative pathways involved in joint development, including Wnt and Notch signaling. This wealth of genomic alteration prompted to identify microRNAs in EVs, 10 of which are associated with RA. As a proof of concept, we focused on miR-455-3p, which was detected in both healthy donor and RA EVs. EV addition to chondrocyte cultures elevated miR-455-3p and exerted anticatabolic effects upon interleukin-1β stimulation; these effects were blocked by actinomycin or miR-455-3p antagomir. Conclusion: Neutrophils from patients with RA yielded EVs with composition, efficacy, and miR-455-3p content similar to those of healthy volunteers, suggesting that neutrophil EVs could be developed as an autologous treatment to protect and repair joint tissue of patients affected by inflammatory arthritides. (Figure presented.).

Original language	English
Pages (from-to)	1705-1718
Number of pages	14
Journal	Arthritis and Rheumatology
Volume	76
Issue number	12
DOIs	https://doi.org/10.1002/art.42958
Publication status	Published - Dec 2024

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Thomas, B. L., Montero-Melendez, T., Oggero, S., Kaneva, M. K., Chambers, D., Pinto, A. L., Nerviani, A., Lucchesi, D., Austin-Williams, S., Hussain, M. T., Pitzalis, C., Allen, B., Malcangio, M., Dell'Accio, F., Norling, L. V., & Perretti, M. (2024). Molecular Determinants of Neutrophil Extracellular Vesicles That Drive Cartilage Regeneration in Inflammatory Arthritis. Arthritis and Rheumatology, 76(12), 1705-1718. https://doi.org/10.1002/art.42958

@article{701aef4220e94fcc845a0439d5a2f2f7,

title = "Molecular Determinants of Neutrophil Extracellular Vesicles That Drive Cartilage Regeneration in Inflammatory Arthritis",

abstract = "Objective: This study was undertaken to establish the potential therapeutic profile of neutrophil-derived extracellular vesicles (EVs) in experimental inflammatory arthritis and associate pharmacological activity with specific EV components, focusing on microRNAs. Methods: Neutrophil EVs were administered intra-articularly through a prophylactic or therapeutic protocol to male C57BL/6 mice undergoing serum-transfer–induced inflammatory arthritis. Transcriptomic analysis of knees was performed on joints following EV administration, naive and arthritic mice (untreated; n = 4/group) and EV-treated diseased mice (intra-articular administration) with contralateral (vehicle-treated; n = 8/group). Comparison of healthy donor and patients with rheumatoid arthritis (RA) neutrophil EVs was performed. Results: EVs afforded cartilage protection with an increase in collagen-II and reduced collagen-X expression within the joint. To gain mechanistic insights, RNA sequencing of the arthritic joints was conducted. A total of 5,231 genes were differentially expressed (P < 0.05), with 257 unique to EV treatment. EVs affected key regenerative pathways involved in joint development, including Wnt and Notch signaling. This wealth of genomic alteration prompted to identify microRNAs in EVs, 10 of which are associated with RA. As a proof of concept, we focused on miR-455-3p, which was detected in both healthy donor and RA EVs. EV addition to chondrocyte cultures elevated miR-455-3p and exerted anticatabolic effects upon interleukin-1β stimulation; these effects were blocked by actinomycin or miR-455-3p antagomir. Conclusion: Neutrophils from patients with RA yielded EVs with composition, efficacy, and miR-455-3p content similar to those of healthy volunteers, suggesting that neutrophil EVs could be developed as an autologous treatment to protect and repair joint tissue of patients affected by inflammatory arthritides. (Figure presented.).",

author = "Thomas, {Bethan L.} and Trinidad Montero-Melendez and Silvia Oggero and Kaneva, {Magdalena K.} and David Chambers and Pinto, {Andreia L.} and Alessandra Nerviani and Davide Lucchesi and Shani Austin-Williams and Hussain, {Mohammed T.} and Costantino Pitzalis and Benjamin Allen and Marzia Malcangio and Francesco Dell'Accio and Norling, {Lucy V.} and Mauro Perretti",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.",

year = "2024",

month = dec,

doi = "10.1002/art.42958",

language = "English",

volume = "76",

pages = "1705--1718",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

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Thomas, BL, Montero-Melendez, T, Oggero, S, Kaneva, MK, Chambers, D, Pinto, AL, Nerviani, A, Lucchesi, D, Austin-Williams, S, Hussain, MT, Pitzalis, C, Allen, B , Malcangio, M, Dell'Accio, F, Norling, LV & Perretti, M 2024, 'Molecular Determinants of Neutrophil Extracellular Vesicles That Drive Cartilage Regeneration in Inflammatory Arthritis', Arthritis and Rheumatology, vol. 76, no. 12, pp. 1705-1718. https://doi.org/10.1002/art.42958

TY - JOUR

T1 - Molecular Determinants of Neutrophil Extracellular Vesicles That Drive Cartilage Regeneration in Inflammatory Arthritis

AU - Thomas, Bethan L.

AU - Montero-Melendez, Trinidad

AU - Oggero, Silvia

AU - Kaneva, Magdalena K.

AU - Chambers, David

AU - Pinto, Andreia L.

AU - Nerviani, Alessandra

AU - Lucchesi, Davide

AU - Austin-Williams, Shani

AU - Hussain, Mohammed T.

AU - Pitzalis, Costantino

AU - Allen, Benjamin

AU - Malcangio, Marzia

AU - Dell'Accio, Francesco

AU - Norling, Lucy V.

AU - Perretti, Mauro

PY - 2024/12

Y1 - 2024/12

N2 - Objective: This study was undertaken to establish the potential therapeutic profile of neutrophil-derived extracellular vesicles (EVs) in experimental inflammatory arthritis and associate pharmacological activity with specific EV components, focusing on microRNAs. Methods: Neutrophil EVs were administered intra-articularly through a prophylactic or therapeutic protocol to male C57BL/6 mice undergoing serum-transfer–induced inflammatory arthritis. Transcriptomic analysis of knees was performed on joints following EV administration, naive and arthritic mice (untreated; n = 4/group) and EV-treated diseased mice (intra-articular administration) with contralateral (vehicle-treated; n = 8/group). Comparison of healthy donor and patients with rheumatoid arthritis (RA) neutrophil EVs was performed. Results: EVs afforded cartilage protection with an increase in collagen-II and reduced collagen-X expression within the joint. To gain mechanistic insights, RNA sequencing of the arthritic joints was conducted. A total of 5,231 genes were differentially expressed (P < 0.05), with 257 unique to EV treatment. EVs affected key regenerative pathways involved in joint development, including Wnt and Notch signaling. This wealth of genomic alteration prompted to identify microRNAs in EVs, 10 of which are associated with RA. As a proof of concept, we focused on miR-455-3p, which was detected in both healthy donor and RA EVs. EV addition to chondrocyte cultures elevated miR-455-3p and exerted anticatabolic effects upon interleukin-1β stimulation; these effects were blocked by actinomycin or miR-455-3p antagomir. Conclusion: Neutrophils from patients with RA yielded EVs with composition, efficacy, and miR-455-3p content similar to those of healthy volunteers, suggesting that neutrophil EVs could be developed as an autologous treatment to protect and repair joint tissue of patients affected by inflammatory arthritides. (Figure presented.).

AB - Objective: This study was undertaken to establish the potential therapeutic profile of neutrophil-derived extracellular vesicles (EVs) in experimental inflammatory arthritis and associate pharmacological activity with specific EV components, focusing on microRNAs. Methods: Neutrophil EVs were administered intra-articularly through a prophylactic or therapeutic protocol to male C57BL/6 mice undergoing serum-transfer–induced inflammatory arthritis. Transcriptomic analysis of knees was performed on joints following EV administration, naive and arthritic mice (untreated; n = 4/group) and EV-treated diseased mice (intra-articular administration) with contralateral (vehicle-treated; n = 8/group). Comparison of healthy donor and patients with rheumatoid arthritis (RA) neutrophil EVs was performed. Results: EVs afforded cartilage protection with an increase in collagen-II and reduced collagen-X expression within the joint. To gain mechanistic insights, RNA sequencing of the arthritic joints was conducted. A total of 5,231 genes were differentially expressed (P < 0.05), with 257 unique to EV treatment. EVs affected key regenerative pathways involved in joint development, including Wnt and Notch signaling. This wealth of genomic alteration prompted to identify microRNAs in EVs, 10 of which are associated with RA. As a proof of concept, we focused on miR-455-3p, which was detected in both healthy donor and RA EVs. EV addition to chondrocyte cultures elevated miR-455-3p and exerted anticatabolic effects upon interleukin-1β stimulation; these effects were blocked by actinomycin or miR-455-3p antagomir. Conclusion: Neutrophils from patients with RA yielded EVs with composition, efficacy, and miR-455-3p content similar to those of healthy volunteers, suggesting that neutrophil EVs could be developed as an autologous treatment to protect and repair joint tissue of patients affected by inflammatory arthritides. (Figure presented.).

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U2 - 10.1002/art.42958

DO - 10.1002/art.42958

M3 - Article

C2 - 39041647

AN - SCOPUS:85201258266

SN - 2326-5191

VL - 76

SP - 1705

EP - 1718

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

IS - 12

ER -

Molecular Determinants of Neutrophil Extracellular Vesicles That Drive Cartilage Regeneration in Inflammatory Arthritis

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