Heme Amplifies the Innate Immune Response to Microbial Molecules through Spleen Tyrosine Kinase (Syk)-dependent Reactive Oxygen Species Generation

• Published in: The Journal of biological chemistry Vol. 285; no. 43; pp. 32844 - 32851
• Main Authors: Fernandez, Patricia L., Dutra, Fabianno F., Alves, Letícia, Figueiredo, Rodrigo T., Mourão-Sa, Diego, Fortes, Guilherme B., Bergstrand, Sophie, Lönn, David, Cevallos, Ricardo R., Pereira, Renata M.S., Lopes, Ulisses G., Travassos, Leonardo H., Paiva, Claudia N., Bozza, Marcelo T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.10.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cytokine Induction; Cytokines - immunology; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Heme; Heme - agonists; Heme - immunology; Heme - metabolism; Heme - pharmacology; Hemolysis; Humans; Immunity, Innate - drug effects; Immunity, Innate - physiology; Immunology; Inflammation; Innate Immunity; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins - metabolism; Lipopolysaccharides - agonists; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Mice, Knockout; NF-kappa B - genetics; NF-kappa B - immunology; NF-kappa B - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - immunology; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase C - genetics; Protein Kinase C - immunology; Protein Kinase C - metabolism; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - immunology; Protein-Tyrosine Kinases - metabolism; Reactive Oxygen Species - immunology; Reactive Oxygen Species - metabolism; Signal Transduction; Syk Kinase; Toll-like Receptors (TLR); Toll-like Receptors (TLR); Hemolysis; Cytokine Induction; Inflammation; Heme; Innate Immunity
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.146076

Infectious diseases that cause hemolysis are among the most threatening human diseases, because of severity and/or global distribution. In these conditions, hemeproteins and heme are released, but whether heme affects the inflammatory response to microorganism molecules remains to be characterized. Here, we show that heme increased the lethality and cytokine secretion induced by LPS in vivo and enhanced the secretion of cytokines by macrophages stimulated with various agonists of innate immune receptors. Activation of nuclear factor κB (NF-κB) and MAPKs and the generation of reactive oxygen species were essential to the increase in cytokine production induced by heme plus LPS. This synergistic effect of heme and LPS was blocked by a selective inhibitor of spleen tyrosine kinase (Syk) and was abrogated in dendritic cells deficient in Syk. Moreover, inhibition of Syk and the downstream molecules PKC and PI3K reduced the reactive oxygen species generation by heme. Our results highlight a mechanism by which heme amplifies the secretion of cytokines triggered by microbial molecule activation and indicates possible pathways for therapeutic intervention during hemolytic infectious diseases.