Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion.
TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production of IL-10 required TLR9 and reduced liver injury. In addition, we found that inflammatory monocytes recruited to the liver via chemokine receptor 2 were downstream targets of cDC IL-10. IL-10 from cDCs reduced production of TNF, IL-6, and ROS by inflammatory monocytes. Our results implicate inflammatory monocytes as mediators of liver I/R injury and reveal that cDCs respond to DAMPS during sterile inflammation, providing the host with protection from progressive tissue damage.
Bamboat
Zubin M
ZM
Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York 10065, USA.
Ocuin
Lee M
LM
Balachandran
Vinod P
VP
Obaid
Hebroon
H
Plitas
George
G
DeMatteo
Ronald P
RP
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D022781:Hepatocytes / Q000502:physiology; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000502:physiology; D054390:Receptors, CCR2 / Q000502:physiology; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051217:Toll-Like Receptor 9 / Q000276:immunology
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D054390:Receptors, CCR2; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D004247:DNA