Scavenger receptor A1 is required for sensing HCMV by endosomal TLR-3/-9 in monocytic THP-1 cells.
Monocytes provide initial surveillance for pathogenic glycopeptides via scavenger receptors (SRs) and for viruses via Toll-like receptors (TLRs) which trigger pro-inflammatory response. However, specific interactions between SR-A1 and TLRs have not yet been assessed in human cytomegalovirus (HCMV)-exposed monocytes. Our results showed two patterns of gene expression upon HCMV exposure: genes that were induced within 10 min include SR-A1, Lyn, TLR-2, and IL-12p35, whereas those induced at 1h are TLR-3, TLR-9, TRIF, IRF-3, and IFN-beta. NF-kappaB p65 and TNF-alpha were elevated at both 10 min and 1h post exposure. Further, inhibitory studies using neutralizing antibodies and morpholino antisense oligonucleotides suggested that within 10 min of HCMV exposure, transcription of TNF-alpha and IL-12 genes is TLR-2-dependent fashion. However, induction of both TLR-3-mediated IFN-beta and TLR-9-mediated TNF-alpha at 1h was dependent on SR-A1. These findings reveal a novel mechanistic insight into an interrelationship between SR-A1 and TLR-3/-9 signaling in HCMV-exposed monocytes.
Yew
Kok-Hooi
KH
Pediatric Infectious Disease, Children's Mercy Hospitals, Kansas City, MO, United States.
Carsten
Bonnie
B
Harrison
Christopher
C
D019138:Antibodies, Blocking / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003587:Cytomegalovirus / Q000187:drug effects / Q000276:immunology*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D018448:Models, Immunological; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*
D019138:Antibodies, Blocking; D016207:Cytokines; C495139:MSR1 protein, human; D016376:Oligonucleotides, Antisense; D051117:Scavenger Receptors, Class A; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9