PMID- 30254055 OWN - NLM STAT- MEDLINE DCOM- 20191031 LR - 20240314 IS - 1937-9145 (Electronic) IS - 1945-0877 (Print) IS - 1945-0877 (Linking) VI - 11 IP - 549 DP - 2018 Sep 25 TI - MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. LID - 10.1126/scisignal.aar3721 [doi] LID - eaar3721 AB - Inflammation resolution counterbalances excessive inflammation and restores tissue homeostasis after injury. Failure of resolution contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated by endogenous specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids by lipoxygenase (LOX) enzymes. 5-LOX plays a critical role in the biosynthesis of two classes of SPMs: lipoxins and resolvins. Cytoplasmic localization of the nonphosphorylated form of 5-LOX is essential for SPM biosynthesis, whereas nuclear localization of phosphorylated 5-LOX promotes proinflammatory leukotriene production. We previously showed that MerTK, an efferocytosis receptor on macrophages, promotes SPM biosynthesis by increasing the abundance of nonphosphorylated, cytoplasmic 5-LOX. We now show that activation of MerTK in human macrophages led to ERK-mediated expression of the gene encoding sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), which decreased the cytosolic Ca(2+) concentration and suppressed the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). This, in turn, reduced the activities of the mitogen-activated protein kinase (MAPK) p38 and the kinase MK2, resulting in the increased abundance of the nonphosphorylated, cytoplasmic form of 5-LOX and enhanced SPM biosynthesis. In a zymosan-induced peritonitis model, an inflammatory setting in which macrophage MerTK activation promotes resolution, inhibition of ERK activation delayed resolution, which was characterized by an increased number of neutrophils and decreased amounts of SPMs in tissue exudates. These findings contribute to our understanding of how MerTK signaling induces 5-LOX-derived SPM biosynthesis and suggest a therapeutic strategy to boost inflammation resolution in settings where defective resolution promotes disease progression. CI - Copyright (c) 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Cai, Bishuang AU - Cai B AD - Departments of Medicine, Pathology and Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA. bc2586@columbia.edu iat1@columbia.edu. FAU - Kasikara, Canan AU - Kasikara C AD - Departments of Medicine, Pathology and Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA. FAU - Doran, Amanda C AU - Doran AC AUID- ORCID: 0000-0002-1576-6274 AD - Departments of Medicine, Pathology and Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA. FAU - Ramakrishnan, Rajasekhar AU - Ramakrishnan R AD - Department of Pediatrics, Columbia University, New York, NY 10032, USA. FAU - Birge, Raymond B AU - Birge RB AD - Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School Cancer Center, Newark, NJ 07103, USA. FAU - Tabas, Ira AU - Tabas I AUID- ORCID: 0000-0003-3429-1515 AD - Departments of Medicine, Pathology and Cell Biology, and Physiology, Columbia University, New York, NY 10032, USA. bc2586@columbia.edu iat1@columbia.edu. LA - eng GR - R00 DK115778/DK/NIDDK NIH HHS/United States GR - R01 HL127464/HL/NHLBI NIH HHS/United States GR - R01 HL075662/HL/NHLBI NIH HHS/United States GR - K99 DK115778/DK/NIDDK NIH HHS/United States GR - P01 HL087123/HL/NHLBI NIH HHS/United States GR - P30 DK063608/DK/NIDDK NIH HHS/United States GR - R01 HL132412/HL/NHLBI NIH HHS/United States GR - R01 CA165077/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180925 PL - United States TA - Sci Signal JT - Science signaling JID - 101465400 RN - 0 (Inflammation Mediators) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (growth arrest-specific protein 6) RN - EC 1.13.11.34 (Arachidonate 5-Lipoxygenase) RN - EC 2.7.10.1 (MERTK protein, human) RN - EC 2.7.10.1 (c-Mer Tyrosine Kinase) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases) RN - EC 7.2.2.10 (ATP2A2 protein, human) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Arachidonate 5-Lipoxygenase/metabolism MH - Calcium/metabolism MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism MH - Cytoplasm/metabolism MH - Cytosol/metabolism MH - Enzyme Activation MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Gene Expression Regulation, Enzymologic MH - HEK293 Cells MH - Humans MH - Inflammation MH - Inflammation Mediators/metabolism MH - Intercellular Signaling Peptides and Proteins/metabolism MH - Jurkat Cells MH - Macrophages/cytology/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - Monocytes/cytology MH - Neutrophils/metabolism MH - Peritonitis/metabolism MH - Phosphorylation MH - Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism MH - *Signal Transduction MH - c-Mer Tyrosine Kinase/*metabolism PMC - PMC6171110 MID - NIHMS988463 COIS- Competing interests: The authors declare that they have no competing interests. EDAT- 2018/09/27 06:00 MHDA- 2019/11/02 06:00 PMCR- 2019/03/25 CRDT- 2018/09/27 06:00 PHST- 2018/09/27 06:00 [entrez] PHST- 2018/09/27 06:00 [pubmed] PHST- 2019/11/02 06:00 [medline] PHST- 2019/03/25 00:00 [pmc-release] AID - 11/549/eaar3721 [pii] AID - 10.1126/scisignal.aar3721 [doi] PST - epublish SO - Sci Signal. 2018 Sep 25;11(549):eaar3721. doi: 10.1126/scisignal.aar3721.