Mitochondrial-mediated inflammation and platelet activation in giant cell arteritis

Despina Michailidou¹, Peter C Grayson², Payton Hermanson³, Jorge Armando Gonzalez Chapa³, David Cuthbertson⁴, Nader A Khalidi⁵, Curry L Koening⁶, Carol A Langford⁷, Carol A McAlear⁸, Larry W Moreland⁹, Christian Pagnoux¹⁰, Philip Seo¹¹, Antoine G Sreih⁸, Kenneth J Warrington¹², Paul A Monach¹³, Peter A Merkel⁸, Christian Lood¹⁴

Affiliations

¹ Division of Rheumatology, University of Washington, Seattle, WA, USA; Division of Rheumatology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA; Division of Rheumatology, Oklahoma City VA Health Care System, Oklahoma, OK, USA.
² Systemic Autoimmunity Branch, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA.
³ Division of Rheumatology, University of Washington, Seattle, WA, USA.
⁴ Health Informatics Institute, University of South Florida, South Florida, FL, USA.
⁵ Division of Rheumatology, Mc Master University, Ontario, Canada.
⁶ Division of Rheumatology, UT Health Austin, Austin, TX, USA.
⁷ Division of Rheumatology, Cleveland Clinic, Cleveland, OH, USA.
⁸ Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Division of Rheumatology and Clinical Immunology, University of Colorado, Denver, CO, USA.
¹⁰ Division of Rheumatology, Mount Sinai Hospital, Toronto, Canada.
¹¹ Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.
¹² Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
¹³ Division of Rheumatology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁴ Division of Rheumatology, University of Washington, Seattle, WA, USA. Electronic address: loodc@uw.edu.

PMID: 37625669
PMCID: PMC10543636
DOI: 10.1016/j.clim.2023.109746

Mitochondrial-mediated inflammation and platelet activation in giant cell arteritis

Despina Michailidou et al. Clin Immunol. 2023 Oct.

. 2023 Oct:255:109746.

doi: 10.1016/j.clim.2023.109746. Epub 2023 Aug 23.

Authors

Affiliations

¹ Division of Rheumatology, University of Washington, Seattle, WA, USA; Division of Rheumatology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA; Division of Rheumatology, Oklahoma City VA Health Care System, Oklahoma, OK, USA.
² Systemic Autoimmunity Branch, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA.
³ Division of Rheumatology, University of Washington, Seattle, WA, USA.
⁴ Health Informatics Institute, University of South Florida, South Florida, FL, USA.
⁵ Division of Rheumatology, Mc Master University, Ontario, Canada.
⁶ Division of Rheumatology, UT Health Austin, Austin, TX, USA.
⁷ Division of Rheumatology, Cleveland Clinic, Cleveland, OH, USA.
⁸ Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Division of Rheumatology and Clinical Immunology, University of Colorado, Denver, CO, USA.
¹⁰ Division of Rheumatology, Mount Sinai Hospital, Toronto, Canada.
¹¹ Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.
¹² Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
¹³ Division of Rheumatology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁴ Division of Rheumatology, University of Washington, Seattle, WA, USA. Electronic address: loodc@uw.edu.

PMID: 37625669
PMCID: PMC10543636
DOI: 10.1016/j.clim.2023.109746

Abstract

Markers of extracellular mitochondria are present in giant cell arteritis (GCA) patients. However, their role in promoting inflammation and platelet activation is no known. To investigate this, isolated mitochondria were opsonized with plasma from GCA patients or healthy individuals and incubated with peripheral blood mononuclear cells (PBMCs) or platelets and assessed for inflammatory cytokine production and platelet activation. Plasma from GCA patients promoted increased mitochondrial-mediated cytokine production by PBMCs as compared to healthy controls (p < 0.05). Mitochondria opsonized with plasma factors from patients with GCA induced higher platelet activation as compared to mitochondria opsonized with plasma factors from healthy individuals (p = 0.0015). Platelet levels of P-selectin were associated with disease activity in GCA (r = 0.34, p = 0.01). GCA patients have impaired ability to regulate the clearance of extracellular mitochondria, possibly contributing to excessive inflammation and platelet activation. Targeting key drivers of mitochondrial extrusion and/or their clearance could lead to new therapeutic interventions in GCA.

Keywords: Cytokines; Giant cell arteritis; Mitochondria; P-selectin; PBMC; Platelets.

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Conflict of interest statement

Declaration of Competing Interest Dr. Michailidou received Advisory Board fees from ChemoCentryx. Dr. Khalidi received clinical trial support from BMS, Sanofi and Abbvie, travel support from Astra Zeneca, and Advisory Board fee from Roche. Dr. Koening served on the advisory board for Chemocentryx and Genentech. Dr. Sreih works at Bristol-Myers Squibb and owns Astra Zeneca and Alexion stock. Dr. Warrington received clinical trial support from Eli Lilly, BMS and Kiniksa, and consulting fees from Chemocentryx. Dr. Monach received consulting fees from Kiniksa, Celgene/BMC, and ChemoCentryx. Dr. Merkel reports receiving funds for the following activities: Consulting and Research Support: AbbVie, Amgen, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, InflaRx, Takeda. Consulting only: ArGenx, Cabaletta, CSL Behring, HiBio, Janssen, Jubilant, Kyverna, MiroBio, Novartis, NS Pharma, Q32, Regeneron, Sparrow, Vistera. Research Support only: Eicos, Electra, Forbius, Genentech/Roche, Genzyme/Sanofi, Neutrolis. Stock options: Kyverna. Royalties: UpToDate. Dr. Lood received research funding from Pfizer, Gilead Sciences, Boehringer Ingelheim, Redd Pharma, Amytryx, and Eli Lilly.

Figures

**Figure 1.. Mitochondrial-mediated cytokine production by PBMCs in giant cell arteritis.**
Levels of IL-1β (A), IL-6 (B), IL-8 (C) and TNF-α (D) upon activation of PBMCs with mitochondria (mito) opsonized with plasma from patients with giant cell arteritis (GCA, (n=66), or healthy controls (HC, n=19). Statistical analyses were performed by Mann-Whitney U test. Each circle represents an individual sample with the bar representing the median of the group. The dotted line represents the cytokine induction by non-opsonized mitochondria. No induction of TNF-alpha was observed for non-opsonized mitochondria.

**Figure 2.. Mitochondrial-mediated platelet activation in giant cell arteritis.**
A) P-selectin expression on platelets was measured by flow cytometry after platelet-rich plasma from a healthy individual was exposed to mitochondria (mito) in the presence of plasma of patients with giant cell arteritis (GCA, (n=58) or healthy controls (HC, n=10). Results are presented as the mean fluorescence intensity (MFI). B) Representative histogram illustrating platelet activation (P-selectin) as measured by flow cytometry upon incubation with ADP (green), or mitochondria opsonized with medium control (black), plasma from healthy control (blue) or plasma from patient with GCA (red). The histograms are normalized to mode with 100 being equal to peak levels for visualization. C) Correlation analysis between Physician Global Assessment (PGA) and in vitro-induction of P-selectin on platelets from patients with GCA. Statistical analyses by Mann-Whitney U test (A) and Spearman’s correlation (C). The dotted line (A) represents the induction of P-selectin by non-opsonized mitochondria.

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References

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Mitochondrial-mediated inflammation and platelet activation in giant cell arteritis

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Mitochondrial-mediated inflammation and platelet activation in giant cell arteritis

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