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Eculizumab treatment alters the proteometabolome beyond the inhibition of complement.
JCI Insight. 2023 Jul 10; 8(13)JI

Abstract

Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target effects shaping long-term outcomes. For this reason, we studied a cohort of patients with MG treated with either eculizumab or azathioprine as well as treatment-naive patients using a combined proteomics and metabolomics approach. This strategy validated known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients, including the oxidative stress response, mitogen-activated protein kinase signaling, and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct off-target effects induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.

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Authors+Show Affiliations

Nelke C
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Schroeter CB
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Stascheit F
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Neurology and Experimental Neurology, Berlin, Germany. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Neuroscience Clinical Research Center, Berlin, Germany.
Huntemann N
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Pawlitzki M
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Willison A
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Räuber S
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Melzer N
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Distler U
University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.
Tenzer S
University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany. Helmholtz Institute for Translational Oncology (HI-TRON) Mainz, Germany. Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
Stühler K
Molecular Proteomics Laboratory, Heinrich Heine University, Düsseldorf, Germany.
Roos A
Department of Neuropediatrics, University of Duisburg-Essen, Essen, Germany.
Meisel A
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Neurology and Experimental Neurology, Berlin, Germany. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Neuroscience Clinical Research Center, Berlin, Germany. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Center for Stroke Research Berlin, Berlin, Germany.
Meuth SG
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Ruck T
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

MeSH

HumansComplement C5Complement System ProteinsComplement ActivationMyasthenia GravisReceptor, Anaphylatoxin C5aLeukotrienes

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

37227781

Citation

Nelke, Christopher, et al. "Eculizumab Treatment Alters the Proteometabolome Beyond the Inhibition of Complement." JCI Insight, vol. 8, no. 13, 2023.
Nelke C, Schroeter CB, Stascheit F, et al. Eculizumab treatment alters the proteometabolome beyond the inhibition of complement. JCI Insight. 2023;8(13).
Nelke, C., Schroeter, C. B., Stascheit, F., Huntemann, N., Pawlitzki, M., Willison, A., Räuber, S., Melzer, N., Distler, U., Tenzer, S., Stühler, K., Roos, A., Meisel, A., Meuth, S. G., & Ruck, T. (2023). Eculizumab treatment alters the proteometabolome beyond the inhibition of complement. JCI Insight, 8(13). https://doi.org/10.1172/jci.insight.169135
Nelke C, et al. Eculizumab Treatment Alters the Proteometabolome Beyond the Inhibition of Complement. JCI Insight. 2023 07 10;8(13) PubMed PMID: 37227781.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Eculizumab treatment alters the proteometabolome beyond the inhibition of complement. AU - Nelke,Christopher, AU - Schroeter,Christina B, AU - Stascheit,Frauke, AU - Huntemann,Niklas, AU - Pawlitzki,Marc, AU - Willison,Alice, AU - Räuber,Saskia, AU - Melzer,Nico, AU - Distler,Ute, AU - Tenzer,Stefan, AU - Stühler,Kai, AU - Roos,Andreas, AU - Meisel,Andreas, AU - Meuth,Sven G, AU - Ruck,Tobias, Y1 - 2023/07/10/ PY - 2023/01/24/received PY - 2023/05/23/accepted PY - 2023/7/11/medline PY - 2023/5/25/pubmed PY - 2023/5/25/entrez KW - Autoimmune diseases KW - Autoimmunity KW - Complement KW - Neuromuscular disease KW - Neuroscience JF - JCI insight JO - JCI Insight VL - 8 IS - 13 N2 - Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target effects shaping long-term outcomes. For this reason, we studied a cohort of patients with MG treated with either eculizumab or azathioprine as well as treatment-naive patients using a combined proteomics and metabolomics approach. This strategy validated known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients, including the oxidative stress response, mitogen-activated protein kinase signaling, and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct off-target effects induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes. SN - 2379-3708 UR - https://www.unboundmedicine.com/medline/citation/37227781 DB - PRIME DP - Unbound Medicine ER -
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