TY - JOUR
T1 - Macrophages use apoptotic cell-derived methionine and DNMT3A during efferocytosis to promote tissue resolution
AU - Ampomah, Patrick B.
AU - Cai, Bishuang
AU - Sukka, Santosh R.
AU - Gerlach, Brennan D.
AU - Yurdagul, Arif
AU - Wang, Xiaobo
AU - Kuriakose, George
AU - Darville, Lancia N.F.
AU - Sun, Yan
AU - Sidoli, Simone
AU - Koomen, John M.
AU - Tall, Alan R.
AU - Tabas, Ira
N1 - Funding Information:
We thank S. Mukherjee and A. Burke (Columbia University) for the Dnmt3aVav1Cre mice; R. Bowman and R. Levine (Memorial Sloan Kettering Cancer Center) for initial discussions about the experimental approach using Dnmt3a-targeted mice; and J. Wang and X. Huang (Columbia) for initial discussions on DNA methylation assays. We acknowledge C. Lu of the Columbia Center for Translational Immunology Core Facility for assisting in the flow cytometry and immunofluorescent imaging experiments, which were conducted in the Columbia Center for Translational Immunology Core Facility, funded by NIH grants P30CA013696, S10OD020056 and S10RR027050. This study was funded by a Transatlantic Network of Excellence (TNE-18CVD04) grant from the Leducq Foundation (to A.R.T. and I.T.) and by the following NIH grants: R00 DK115778 (to B.C.); T32 5T32HL007343-42 (to B.D.G.); K99 HL145131 (to A.Y.); R01 HL127464 (to I.T.); and R01 HL087123 and R35 HL145228 (to I.T.). B.C. received funding support from R00DK115778. S.S. and Y.S. acknowledge the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant); AFAR (Sagol Network GerOmic Award); the Einstein Nathan Shock Center for the Biology of Aging, Deerfield (Xseed award); NIH P30 grant CA01333047; shared instrument grant NIH 1 S10 OD030286-01; and NIGMS grant 5 R01GM129350-04 (PI: Brenowitz). This work has also been supported in part by the Proteomics & Metabolomics Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). fl/fl +/–
Funding Information:
We thank S. Mukherjee and A. Burke (Columbia University) for the Dnmt3afl/fl Vav1Cre+/? mice; R. Bowman and R. Levine (Memorial Sloan Kettering Cancer Center) for initial discussions about the experimental approach using Dnmt3a -targeted mice; and J. Wang and X. Huang (Columbia) for initial discussions on DNA methylation assays. We acknowledge C. Lu of the Columbia Center for Translational Immunology Core Facility for assisting in the flow cytometry and immunofluorescent imaging experiments, which were conducted in the Columbia Center for Translational Immunology Core Facility, funded by NIH grants P30CA013696, S10OD020056 and S10RR027050. This study was funded by a Transatlantic Network of Excellence (TNE-18CVD04) grant from the Leducq Foundation (to A.R.T. and I.T.) and by the following NIH grants: R00 DK115778 (to B.C.); T32 5T32HL007343-42 (to B.D.G.); K99 HL145131 (to A.Y.); R01 HL127464 (to I.T.); and R01 HL087123 and R35 HL145228 (to I.T.). B.C. received funding support from R00DK115778. S.S. and Y.S. acknowledge the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant); AFAR (Sagol Network GerOmic Award); the Einstein Nathan Shock Center for the Biology of Aging, Deerfield (Xseed award); NIH P30 grant CA01333047; shared instrument grant NIH 1 S10 OD030286-01; and NIGMS grant 5 R01GM129350-04 (PI: Brenowitz). This work has also been supported in part by the Proteomics & Metabolomics Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4
Y1 - 2022/4
N2 - Efferocytosis, the clearance of apoptotic cells (ACs) by macrophages, is critical for tissue resolution, with defects driving many diseases. Mechanisms of efferocytosis-mediated resolution are incompletely understood. Here, we show that AC-derived methionine regulates resolution through epigenetic repression of the extracellular signal-regulated kinase 1/2 (ERK1/2) phosphatase Dusp4. We focus on two key efferocytosis-induced pro-resolving mediators, prostaglandin E2 (PGE2) and transforming growth factor beta 1 (TGF-β1), and show that efferocytosis induces prostaglandin-endoperoxide synthase 2/cyclooxygenase 2 (Ptgs2/COX2), leading to PGE2 synthesis and PGE2-mediated induction of TGF-β1. ERK1/2 phosphorylation/activation by AC-activated CD36 is necessary for Ptgs2 induction, but this is insufficient owing to an ERK−DUSP4 negative feedback pathway that lowers phospho-ERK. However, subsequent AC engulfment and phagolysosomal degradation lead to Dusp4 repression, enabling enhanced p-ERK and induction of the Ptgs2−PGE2−TGF-β1 pathway. Mechanistically, AC-derived methionine is converted to S-adenosylmethionine, which is used by DNA methyltransferase-3A (DNMT3A) to methylate Dusp4. Bone-marrow DNMT3A deletion in mice blocks COX2/PGE2, TGF-β1, and resolution in sterile peritonitis, apoptosis-induced thymus injury and atherosclerosis. Knowledge of how macrophages use AC-cargo and epigenetics to induce resolution provides mechanistic insight and therapeutic options for diseases driven by impaired resolution.
AB - Efferocytosis, the clearance of apoptotic cells (ACs) by macrophages, is critical for tissue resolution, with defects driving many diseases. Mechanisms of efferocytosis-mediated resolution are incompletely understood. Here, we show that AC-derived methionine regulates resolution through epigenetic repression of the extracellular signal-regulated kinase 1/2 (ERK1/2) phosphatase Dusp4. We focus on two key efferocytosis-induced pro-resolving mediators, prostaglandin E2 (PGE2) and transforming growth factor beta 1 (TGF-β1), and show that efferocytosis induces prostaglandin-endoperoxide synthase 2/cyclooxygenase 2 (Ptgs2/COX2), leading to PGE2 synthesis and PGE2-mediated induction of TGF-β1. ERK1/2 phosphorylation/activation by AC-activated CD36 is necessary for Ptgs2 induction, but this is insufficient owing to an ERK−DUSP4 negative feedback pathway that lowers phospho-ERK. However, subsequent AC engulfment and phagolysosomal degradation lead to Dusp4 repression, enabling enhanced p-ERK and induction of the Ptgs2−PGE2−TGF-β1 pathway. Mechanistically, AC-derived methionine is converted to S-adenosylmethionine, which is used by DNA methyltransferase-3A (DNMT3A) to methylate Dusp4. Bone-marrow DNMT3A deletion in mice blocks COX2/PGE2, TGF-β1, and resolution in sterile peritonitis, apoptosis-induced thymus injury and atherosclerosis. Knowledge of how macrophages use AC-cargo and epigenetics to induce resolution provides mechanistic insight and therapeutic options for diseases driven by impaired resolution.
UR - http://www.scopus.com/inward/record.url?scp=85127419811&partnerID=8YFLogxK
U2 - 10.1038/s42255-022-00551-7
DO - 10.1038/s42255-022-00551-7
M3 - Article
C2 - 35361955
AN - SCOPUS:85127419811
SN - 2522-5812
VL - 4
SP - 444
EP - 457
JO - Nature Metabolism
JF - Nature Metabolism
IS - 4
ER -