TY - JOUR
T1 - MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity
AU - Cai, Bishuang
AU - Kasikara, Canan
AU - Doran, Amanda C.
AU - Ramakrishnan, Rajasekhar
AU - Birge, Raymond B.
AU - Tabas, Ira
N1 - Publisher Copyright:
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2018/9/25
Y1 - 2018/9/25
N2 - 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 Ca2+ 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.
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 Ca2+ 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.
UR - http://www.scopus.com/inward/record.url?scp=85054003958&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aar3721
DO - 10.1126/scisignal.aar3721
M3 - Article
C2 - 30254055
AN - SCOPUS:85054003958
SN - 1945-0877
VL - 11
JO - Science Signaling
JF - Science Signaling
IS - 549
M1 - aar3721
ER -