Mechanism and regulatory function of CpG signaling via scavenger receptor B1 in primary B cells.
It is well established that CpG promotes pro-inflammatory cytokine and antibody production by B cells via the Toll-like receptor 9 (TLR9)-dependent pathway. However, scavenger receptors (SRs) are also capable of binding such pathogen-derived molecules, yet their contribution to CpG-induced signaling events has not yet been evaluated. Here we identified a novel TLR9-independent mechanism of CpG-induced signaling and immune function that is mediated by the scavenger B1 receptor (SR-B1). Specifically, we show that CpG/SR-B1 triggers calcium entry into primary B lymphocytes via phospholipase C gamma-1-mediated activation of TRPC3 channels and also B cell adhesion to vascular cell adhesion molecule-1. CpG-induced calcium signals and vascular cell adhesion molecule-1 adhesion are TLR9-independent and are mediated exclusively by SR-B1. Although pro-inflammatory cytokine and Ig production induced by CpG require TLR9 expression, we also found that SR-B1 negatively regulates TLR9-dependent production of interleukin-6, interleukin-10, and IgM. Thus, our results provide a novel perspective on the complexity of CpG signaling within B cells by demonstrating that SR-B1 is an alternative pathway for nucleic acid-induced signaling that provides feedback inhibition on specific TLR9-dependent responses of B cells. Consequently, these results have wide implications for understanding the mechanisms regulating immune tolerance to nucleic acids and pathogen-associated molecules.
Zhu
Peimin
P
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6010, USA.
Liu
Xiaohong
X
Treml
Laura S
LS
Cancro
Michael P
MP
Freedman
Bruce D
BD
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015226:Dinucleoside Phosphates / Q000494:pharmacology / Q000502:physiology*; D004594:Electrophysiology; D006801:Humans; D016753:Interleukin-10; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050052:TRPC Cation Channels / Q000235:genetics / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000502:physiology
D000906:Antibodies; D002118:Calcium; D015226:Dinucleoside Phosphates; D016753:Interleukin-10; D051966:Phospholipase C gamma; D051122:Scavenger Receptors, Class B; D050052:TRPC Cation Channels; D051217:Toll-Like Receptor 9; C104603:TRPC3 cation channel; C015772:CpG dinucleotide