A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Ohira, Taisuke; Bannenberg, Gerard; Arita, Makoto; Takahashi, Minoru; Ge, Qingyuan; Dyke, Thomas E. Van; Stahl, Gregory L.; Serhan, Charles N.; Badwey, John A.

doi:10.4049/jimmunol.173.3.2091

Cited by 58 publications

(29 citation statements)

References 54 publications

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“…Interestingly, another study showed that LL-37 stimulated p38 and LTB 4 formation in PMNs (34), although the signal transduction pathway leading to p38 activation was not elucidated. These findings, together with the data herein, suggest that the ability of SPMs to rapidly and transiently limit intracellular calcium and CaMKII-p38-MK2 signaling may be a fundamental mechanism for preventing excessive or prolonged inflammation (33,35).…”

Section: Discussionmentioning

confidence: 75%

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway

Fredman

Özcan

Spolitu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

169

157

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Imbalances between proinflammatory and proresolving mediators can lead to chronic inflammatory diseases. The balance of arachidonic acid-derived mediators in leukocytes is thought to be achieved through intracellular localization of 5-lipoxygenase (5-LOX): nuclear 5-LOX favors the biosynthesis of proinflammatory leukotriene B 4 (LTB 4 ), whereas, in theory, cytoplasmic 5-LOX could favor the biosynthesis of proresolving lipoxin A 4 (LXA 4 ). This balance is shifted in favor of LXA 4 by resolvin D1 (RvD1), a specialized proresolving mediator derived from docosahexaenoic acid, but the mechanism is not known. Here we report a new pathway through which RvD1 promotes nuclear exclusion of 5-LOX and thereby suppresses LTB 4 and enhances LXA 4 in macrophages. RvD1, by activating its receptor formyl peptide receptor2/lipoxin A 4 receptor, suppresses cytosolic calcium and decreases activation of the calcium-sensitive kinase calcium-calmodulin-dependent protein kinase II (CaMKII). CaMKII inhibition suppresses activation P38 and mitogen-activated protein kinase-activated protein kinase 2 kinases, which reduces Ser271 phosphorylation of 5-LOX and shifts 5-LOX from the nucleus to the cytoplasm. As such, RvD1's ability to decrease nuclear 5-LOX and the LTB 4 :LXA 4 ratio in vitro and in vivo was mimicked by macrophages lacking CaMKII or expressing S271A-5-LOX. These findings provide mechanistic insight into how a specialized proresolving mediator from the docosahexaenoic acid pathway shifts the balance toward resolution in the arachidonic acid pathway. Knowledge of this mechanism may provide new strategies for promoting inflammation resolution in chronic inflammatory diseases.P ersistent inflammation and its failed resolution underlie the pathophysiology of prevalent human diseases, including cancer, diabetes, and atherosclerosis (1). Hence, uncovering mechanisms to suppress inflammation and enhance resolution is of immense interest (2-5). Resolution is orchestrated in part by specialized proresolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins (2), and by protein and peptide mediators (6). A common protective function of SPMs is their ability to limit excessive proinflammatory leukotriene formation without being immunosuppressive (2, 7). Specifically, resolvin D1 (RvD1) is protective in several disease models (8) and limits excessive leukotriene B 4 (LTB 4 ) production without compromising host defense (7, 9). However, the mechanism underlying these actions of RvD1 is not well understood.Arachidonic acid (AA) is first converted into 5-hydroperoxyeicosatetraenoicacid (5-HPETE) and then into leukotriene A 4 (LTA 4 ) by 5-lipoxygenase (5-LOX) (10, 11). Subsequent hydrolysis of LTA 4 by LTA 4 hydrolase yields LTB 4 (10, 11). During inflammation, 5-LOX is phosphorylated and translocates to the nuclear membrane, which favors the biosynthesis of LTB 4 (12-17). However, major gaps remain in our understanding of the relevance of this pathway to primary cells and animal models and how they are regulated by...

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Section: Discussionmentioning

confidence: 75%

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway

Fredman

Özcan

Spolitu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

169

157

View full text Add to dashboard Cite

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“…Along these lines, using proteomic analysis, ATLa blocks phosphorylation and activation of leukocyte-specific protein-1 along with several other components of the p38 MAPK pathway in human PMNs. These results indicate a regulatory role for LXA 4 and ATL on the p38 MAPK cascade, which is known to promote chemotaxis and other inflammatory responses (Ohira et al, 2004).…”

Section: Fibroblast: Inhibition Of Proinflammatory Cytokinesmentioning

confidence: 82%

The Lipoxin Receptor ALX: Potent Ligand-Specific and Stereoselective Actions in Vivo

et al. 2006

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“…cAMP is also intrinsically involved in the regulation of cytoskeletal rearrangement and function (12). More recently, it was reported that neutrophils stimulated with the chemoattractant fMLP exhibited intense phosphorylation of a 55-kDa protein that was blocked by ATLa (aspirin-triggered lipoxin) treatment (10 -50 nM) (13). This 55-kDa protein was identified as leukocyte-specific protein 1, a downstream component of the p38-MAPK cascade in neutrophils.…”

mentioning

confidence: 99%

Lipoxin A4 Redistributes Myosin IIA and Cdc42 in Macrophages: Implications for Phagocytosis of Apoptotic Leukocytes

Reville

Crean

Vivers

et al. 2006

The Journal of Immunology

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Lipoxins (LXs) are endogenously produced anti-inflammatory agents that modulate leukocyte trafficking and stimulate nonphlogistic macrophage phagocytosis of apoptotic neutrophils, thereby promoting the resolution of inflammation. Previous data suggest a role for altered protein phosphorylation and cytoskeletal rearrangement in LX-stimulated phagocytosis but the exact mechanisms remain unclear. In this study we examine the effects of LXA4 on the protein phosphorylation pattern of THP-1 cells differentiated into a macrophage-like phenotype. THP-1 cells stimulated with LXA4 (1 nM) exhibit dephosphorylation of a 220-kDa protein. Using mass spectrometry, this protein was identified as MYH9, a nonmuscle myosin H chain II isoform A, which is involved in cytoskeleton rearrangement. THP-1 cells treated with LXA4 adopt a polarized morphology with activated Cdc42 localized toward the leading edge and MYH9 localized at the cell posterior. Polarized distribution of Cdc42 is associated with Akt/PKB-mediated Cdc42 activation. Interestingly, the annexin-derived peptide Ac2–26, a recently described agonist for the LXA4 receptor, also stimulates macrophage phagocytosis, MYH9 dephosphorylation, and MYH9 redistribution. In addition, we demonstrate that LXA4 stimulates the phosphorylation of key polarity organization molecules: Akt, protein kinase Cζ, and glycogen synthase kinase-3β. Inhibition of LXA4-induced Akt and protein kinase Cζ activity with specific inhibitors prevented LXA4-stimulated phagocytosis of both apoptotic polymorphonuclear neutrophils and lymphocytes, highlighting a potential use for LXA4 in the treatment of autoimmune diseases. Furthermore, phosphorylation and subsequent inactivation of glycogen synthase kinase-3β resulted in an increase in phagocytosis similar to that of LXA4. These data highlight an integrated mechanism whereby LXA4 regulates phagocytosis through facilitative actin cytoskeleton rearrangement and cell polarization.

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A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Cited by 58 publications

References 54 publications

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway

The Lipoxin Receptor ALX: Potent Ligand-Specific and Stereoselective Actions in Vivo

Lipoxin A4 Redistributes Myosin IIA and Cdc42 in Macrophages: Implications for Phagocytosis of Apoptotic Leukocytes

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A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Cited by 58 publications

References 54 publications

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B 4 synthesis by inhibiting a calcium-activated kinase pathway

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B 4 synthesis by inhibiting a calcium-activated kinase pathway

The Lipoxin Receptor ALX: Potent Ligand-Specific and Stereoselective Actions in Vivo

Lipoxin A4 Redistributes Myosin IIA and Cdc42 in Macrophages: Implications for Phagocytosis of Apoptotic Leukocytes

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Product

Resources

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Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway