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

Runtsch, Marah C.; Angiari, Stefano; Mendez, Rui Santalla; Zotta, Alessia; Peace, Christian G.; Walsh, Aoife; Chirillo, Roberta; Hams, Emily; Fallon, Padraic G.; Jayamaran, Ranjith; Dua, Kamal; Brown, Alexandra C.; Hooftman, Alexander; Kim, Richard Y.; Horvat, Jay C.; Hansbro, Philip M.; Wang, C; O'Neill, LAJ; Wadhwa, Ridhima; Zhang, Yanling; Zheng, Yunan; Spina, Joseph S.; Ruzek, Melanie C.; Argiriadi, Maria A.; McGettrick, Anne F.

Title: Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages
Creator: Runtsch, Marah C.; Angiari, Stefano; Mendez, Rui Santalla; Zotta, Alessia; Peace, Christian G.; Walsh, Aoife; Chirillo, Roberta; Hams, Emily; Fallon, Padraic G.; Jayamaran, Ranjith; Dua, Kamal; Brown, Alexandra C.; Hooftman, Alexander; Kim, Richard Y.; Horvat, Jay C.; Hansbro, Philip M.; Wang, C; O'Neill, LAJ; Wadhwa, Ridhima; Zhang, Yanling; Zheng, Yunan; Spina, Joseph S.; Ruzek, Melanie C.; Argiriadi, Maria A.; McGettrick, Anne F.
Relation: Cell Metabolism Vol. 34, Issue 3, p. 487-501.e8
Publisher Link: http://dx.doi.org/10.1016/j.cmet.2022.02.002
Publisher: Cell Press
Resource Type: journal article
Date: 2022
Description: 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.
Subject: itaconate; macrophages; M2 macrophage; Jak-STAT; immunometabolism; Krebs cycle
Identifier: http://hdl.handle.net/1959.13/1464456
Identifier: uon:47003
Identifier: ISSN:1550-4131
Language: eng
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