Syk activation is a leukotriene B4-regulated event involved in macrophage phagocytosis of IgG-coated targets but not apoptotic cells.
Macrophages are called upon to ingest both IgG-coated targets and apoptotic cells. Important roles for tyrosine kinase Syk and leukotriene B4 (LTB4) are recognized in FcgammaR-mediated phagocytosis. Here we evaluated the roles of Syk and LTB4 in macrophage phagocytosis of apoptotic thymocytes versus IgG-coated erythrocytes. Macrophage ingestion of apoptotic thymocytes was not influenced by exogenous or endogenous LTB4 nor associated with Syk activation (phosphorylation). By contrast, LTB4 dose-dependently amplified FcgammaR-mediated phagocytosis as well as Syk activation. Furthermore, a role for endogenous LTB4 in Syk activation during FcgammaR-mediated phagocytosis was demonstrated using pharmacologic and genetic abrogation of 5-lipoxygenase. LTB4 was unique among 5-lipoxygenase products in this regard, since LTD4 and 5-hydroxyeicosatetraenoic acid (HETE) were unable to amplify Syk activation in response to FcgammaR engagement. Ca2+ chelation studies revealed that FcgammaR-mediated Syk activation as well as LTB4 amplification thereof was Ca2+ regulated. These 2 parallel phagocytic processes therefore exhibit initial divergence in signal transduction events, with Syk activation being an LTB4-regulated event in FcgammaR-mediated but not apoptotic cell ingestion. As LTB4 is an important proinflammatory product of macrophages, we speculate that this divergence evolved to permit FcgammaR-mediated phagocytosis to proceed in an inflammatory milieu, while apoptotic cell clearance is noninflammatory.
Canetti
Claudio
C
Division of Pulmonary and Critical Care Medicine, 6301 MSRB III, University of Michigan Medical Center, Ann Arbor, MI 48109-0642, USA.
Hu
Bin
B
Curtis
Jeffrey L
JL
Peters-Golden
Marc
M
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007074:Immunoglobulin G / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007975:Leukotriene B4 / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017452:Receptors, IgG / Q000378:metabolism; D000072377:Syk Kinase
D002630:Chemotactic Factors; D004792:Enzyme Precursors; D006893:Hydroxyeicosatetraenoic Acids; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D017452:Receptors, IgG; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000606898:Syk protein, rat; D002118:Calcium