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Lipoxin A₄ Redistributes Myosin IIA and Cdc42 in Macrophages: Implications for Phagocytosis of Apoptotic Leukocytes¹

Keira Reville^*, John K. Crean^*, Sharon Vivers, Ian Dransfield and Catherine Godson^2,*

^* School of Medicine and Medical Sciences, Conway Institute, University College Dublin, Belfield, and the Dublin Molecular Medicine Centre, Dublin, Ireland; and The Rayne Laboratory, Medical Research Council Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh, United Kingdom

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 Ac_2–26, 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 C, and glycogen synthase kinase-3. Inhibition of LXA₄-induced Akt and protein kinase C 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-3 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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