Macrophage interleukin-6 and tumour necrosis factor-alpha are induced by coronavirus fixation to Toll-like receptor 2/heparan sulphate receptors but not carcinoembryonic cell adhesion antigen 1a.
A rapid antiviral immune response may be related to viral interaction with the host cell leading to activation of macrophages via pattern recognition receptors (PPRs) or specific viral receptors. Carcinoembryonic cell adhesion antigen 1a (CEACAM1a) is the specific receptor for the mouse hepatitis virus (MHV), a coronavirus known to induce acute viral hepatitis in mice. The objective of this study was to understand the mechanisms responsible for the secretion of high-pathogenic MHV3-induced inflammatory cytokines. We report that the induction of the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha in peritoneal macrophages does not depend on CEACAM1a, as demonstrated in cells isolated from Ceacam1a(-/-) mice. The induction of IL-6 and TNF-alpha production was related rather to the fixation of the spike (S) protein of MHV3 on Toll-like receptor 2 (TLR2) in regions enriched in heparan sulphate and did not rely on viral replication, as demonstrated with denatured S protein and UV-inactivated virus. High levels of IL-6 and TNF-alpha were produced in livers from infected C57BL/6 mice but not in livers from Tlr2(-/-) mice. The histopathological observations were correlated with the levels of those inflammatory cytokines. Depending on mouse strain, the viral fixation to heparan sulfate/TLR2 stimulated differently the p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB in the induction of IL-6 and TNF-alpha. These results suggest that TLR2 and heparan sulphate receptors can act as new viral PPRs involved in inflammatory responses.
Jacques
Alexandre
A
Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC, Canada.
Bleau
Christian
C
Turbide
Claire
C
Beauchemin
Nicole
N
Lamontagne
Lucie
L
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018352:Coronavirus Infections / Q000150:complications*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006497:Heparan Sulfate / Q000276:immunology / Q000378:metabolism; D006520:Hepatitis, Animal / Q000276:immunology* / Q000821:virology; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000819:agonists / Q000096:biosynthesis; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000276:immunology; D009570:Nitriles / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D064370:Spike Glycoprotein, Coronavirus; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D002070:Butadienes; D002272:Carcinoembryonic Antigen; D004791:Enzyme Inhibitors; D006497:Heparan Sulfate; D007093:Imidazoles; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009570:Nitriles; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D064370:Spike Glycoprotein, Coronavirus; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C486183:Ceacam1 protein, mouse; C113580:U 0126; C578557:spike glycoprotein, SARS-CoV; C578553:spike protein, mouse hepatitis virus; C093642:SB 203580