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.
Division of Pulmonary and Critical Care Medicine, 6301 MSRB III, University of Michigan Medical Center, Ann Arbor, MI 48109-0642, USA.
Claudio
C
Canetti
Bin
B
Hu
Jeffrey L
JL
Curtis
Marc
M
Peters-Golden
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