CD200R1 supports HSV-1 viral replication and licenses pro-inflammatory signaling functions of TLR2.
The CD200R1:CD200 axis is traditionally considered to limit tissue inflammation by down-regulating pro-inflammatory signaling in myeloid cells bearing the receptor. We generated CD200R1(-/-) mice and employed them to explore both the role of CD200R1 in regulating macrophage signaling via TLR2 as well as the host response to an in vivo, TLR2-dependent model, herpes simplex virus 1 (HSV-1) infection. CD200R1(-/-) peritoneal macrophages demonstrated a 70-75% decrease in the generation of IL-6 and CCL5 (Rantes) in response to the TLR2 agonist Pam(2)CSK(4) and to HSV-1. CD200R1(-/-) macrophages could neither up-regulate the expression of TLR2, nor assemble a functional inflammasome in response to HSV-1. CD200R1(-/-) mice were protected from HSV-1 infection and exhibited dysfunctional TLR2 signaling. Finally, both CD200R1(-/-) mice and CD200R1(-/-) fibroblasts and macrophages showed a markedly reduced ability to support HSV-1 replication. In summary, our data demonstrate an unanticipated and novel requirement for CD200R1 in "licensing" pro-inflammatory functions of TLR2 and in limiting viral replication that are supported by ex vivo and in vivo evidence.
Renal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA. Soberman@helix.mgh.harvard.edu
Roy J
RJ
Soberman
Christopher R
CR
MacKay
Christine A
CA
Vaine
Glennice Bowen
GB
Ryan
Anna M
AM
Cerny
Mikayla R
MR
Thompson
Boris
B
Nikolic
Valeria
V
Primo
Peter
P
Christmas
Paul
P
Sheiffele
Lisa
L
Aronov
David M
DM
Knipe
Evelyn A
EA
Kurt-Jones
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology; D004622:Embryo, Mammalian / Q000166:cytology; D004660:Encephalitis / Q000276:immunology / Q000473:pathology / Q000821:virology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018390:Gene Targeting; D018259:Herpesvirus 1, Human / Q000502:physiology*; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D007370:Interferon Type I / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D064446:Orexin Receptors; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D019562:Viral Load / Q000276:immunology; D014779:Virus Replication / Q000502:physiology*
D000954:Antigens, Surface; C501103:Cd200r1 protein, mouse; D007370:Interferon Type I; D064446:Orexin Receptors; D011956:Receptors, Cell Surface; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2