Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages

Marah C Runtsch¹, Stefano Angiari², Alexander Hooftman², Ridhima Wadhwa³, Yanling Zhang⁴, Yunan Zheng⁵, Joseph S Spina⁶, Melanie C Ruzek⁶, Maria A Argiriadi⁶, Anne F McGettrick², Rui Santalla Mendez², Alessia Zotta², Christian G Peace², Aoife Walsh², Roberta Chirillo⁷, Emily Hams⁸, Padraic G Fallon⁸, Ranjith Jayamaran⁹, Kamal Dua³, Alexandra C Brown¹⁰, Richard Y Kim¹¹, Jay C Horvat¹⁰, Philip M Hansbro¹², Chu Wang⁴, Luke A J O'Neill¹³

Affiliations

¹ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland. Electronic address: runtschm@tcd.ie.
² School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland.
³ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.
⁴ Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
⁵ Drug Discovery Science & Technology, AbbVie Inc., 1 North Waukegon Road, North Chicago, IL 60064, USA.
⁶ AbbVie, Bio Research Center, 100 Research Drive, Worcester, MA 01608, USA.
⁷ Department of Experimental and Clinical Medicine, "Magna Græcia" University of Catanzaro, Catanzaro, Italy.
⁸ School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland.
⁹ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
¹⁰ Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia.
¹¹ School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia.
¹² Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia.
¹³ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland. Electronic address: laoneill@tcd.ie.

PMID: 35235776
DOI: 10.1016/j.cmet.2022.02.002

Free article

Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages

Marah C Runtsch et al. Cell Metab. 2022.

Free article

. 2022 Mar 1;34(3):487-501.e8.

doi: 10.1016/j.cmet.2022.02.002.

Authors

Affiliations

¹ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland. Electronic address: runtschm@tcd.ie.
² School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland.
³ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.
⁴ Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
⁵ Drug Discovery Science & Technology, AbbVie Inc., 1 North Waukegon Road, North Chicago, IL 60064, USA.
⁶ AbbVie, Bio Research Center, 100 Research Drive, Worcester, MA 01608, USA.
⁷ Department of Experimental and Clinical Medicine, "Magna Græcia" University of Catanzaro, Catanzaro, Italy.
⁸ School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland.
⁹ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
¹⁰ Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia.
¹¹ School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia.
¹² Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia.
¹³ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland. Electronic address: laoneill@tcd.ie.

PMID: 35235776
DOI: 10.1016/j.cmet.2022.02.002

Abstract

The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory "M1" macrophages. However, alternatively activated "M2" macrophages can take up itaconate. We therefore examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation. We demonstrate that itaconate and OI inhibit M2 polarization and metabolic remodeling. Examination of IL-4 signaling revealed inhibition of JAK1 and STAT6 phosphorylation by both itaconate and OI. JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity. Finally, OI treatment suppressed M2 macrophage polarization and JAK1 phosphorylation in vivo. We therefore identify itaconate and OI as JAK1 inhibitors, suggesting a new strategy to inhibit JAK1 in M2 macrophage-driven diseases.

Keywords: Jak-STAT; Krebs cycle; M2 macrophage; immunometabolism; itaconate; macrophages.

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Conflict of interest statement

Declaration of interests Y. Zheng, J.S.S., M.C. Ruzek, and M.A.A. are employees and shareholders of AbbVie. All other authors declare no competing interests related to this manuscript.

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Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages

Affiliations

Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous