Myeloid heme oxygenase-1 regulates innate immunity and autoimmunity by modulating IFN-beta production.
Heme oxygenase-1 (HO-1) is a key cytoprotective, antioxidant, and antiinflammatory molecule. The pathophysiological functions of HO-1 have been associated with its enzymatic activities in heme catabolism. We have examined the immune functions of HO-1 by its conditional ablation in myeloid cells (HO-1(M-KO) mice). We demonstrate that myeloid HO-1 is required for the activation of interferon (IFN) regulatory factor (IRF) 3 after Toll-like receptor 3 or 4 stimulation, or viral infection. HO-1-deficient macrophages show reduced expression of IFN-beta and of primary IRF3 target genes encoding RANTES, IP-10 and MCP-1. In the presence of polyI:C, myeloid HO-1 knockout mice infected with Listeria monocytogenes, a model dependent on IFN-beta production, showed enhanced bacterial clearance and survival, whereas control mice succumbed to infection. Moreover, after induction of experimental autoimmune encephalomyelitis, mice with myeloid-specific HO-1 deficiency developed a higher incidence and an exacerbated, nonremitting clinical disease correlating with persistent activation of antigen-presenting cells, enhanced infiltration of Th17 cells, and a nonregressing myelin-specific T cell reactivity. Notably, these defects were rectified by exogenous administration of IFN-beta, confirming that HO-1 functions directly upstream of this critical immune pathway. These results uncover a novel direct function for myeloid HO-1 in the regulation of IFN-beta production, establishing HO-1 as a critical early mediator of the innate immune response.
Tzima
Sotiria
S
Biomedical Sciences Research Center Alexander Fleming, Vari 166-72, Greece.
Victoratos
Panayiotis
P
Kranidioti
Ksanthi
K
Alexiou
Maria
M
Kollias
George
G
D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D003433:Crosses, Genetic; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D006706:Homeostasis / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D019426:Integrases / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology / Q000401:mortality; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology*; D017741:Survivors; D051196:Toll-Like Receptor 3 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D051547:Heme Oxygenase-1; C045073:Cre recombinase; D019426:Integrases