TY - JOUR
T1 - In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α
AU - Connolly, Michael K.
AU - Bedrosian, Andrea S.
AU - Mallen-St. Clair, Jon
AU - Mitchell, Aaron P.
AU - Ibrahim, Junaid
AU - Stroud, Andrea
AU - Pachter, H. Leon
AU - Bar-Sagi, Dafna
AU - Frey, Alan B.
AU - Miller, George
PY - 2009/11/2
Y1 - 2009/11/2
N2 - Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue. Because DCs are central to modulating liver immunity, we postulated that altered DC function contributes to immunologic changes in hepatic fibrosis and affects the pathologic inflammatory milieu within the fibrotic liver. Using mouse models, we determined the contribution of DCs to altered hepatic immunity in fibrosis and investigated the role of DCs in modulating the inflammatory environment within the fibrotic liver. We found that DC depletion completely abrogated the elevated levels of many inflammatory mediators that are produced in the fibrotic liver. DCs represented approximately 25% of the fibrotic hepatic leukocytes and showed an elevated CD11b+CD8- fraction, a lower B220+ plasmacytoid fraction, and increased expression of MHC II and CD40. Moreover, after liver injury, DCs gained a marked capacity to induce hepatic stellate cells, NK cells, and T cells to mediate inflammation, proliferation, and production of potent immune responses. The proinflammatory and immunogenic effects of fibrotic DCs were contingent on their production of TNF-α. Therefore, modulating DC function may be an attractive approach to experimental therapeutics in fibro-inflammatory liver disease.
AB - Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue. Because DCs are central to modulating liver immunity, we postulated that altered DC function contributes to immunologic changes in hepatic fibrosis and affects the pathologic inflammatory milieu within the fibrotic liver. Using mouse models, we determined the contribution of DCs to altered hepatic immunity in fibrosis and investigated the role of DCs in modulating the inflammatory environment within the fibrotic liver. We found that DC depletion completely abrogated the elevated levels of many inflammatory mediators that are produced in the fibrotic liver. DCs represented approximately 25% of the fibrotic hepatic leukocytes and showed an elevated CD11b+CD8- fraction, a lower B220+ plasmacytoid fraction, and increased expression of MHC II and CD40. Moreover, after liver injury, DCs gained a marked capacity to induce hepatic stellate cells, NK cells, and T cells to mediate inflammation, proliferation, and production of potent immune responses. The proinflammatory and immunogenic effects of fibrotic DCs were contingent on their production of TNF-α. Therefore, modulating DC function may be an attractive approach to experimental therapeutics in fibro-inflammatory liver disease.
UR - http://www.scopus.com/inward/record.url?scp=70449355084&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70449355084&partnerID=8YFLogxK
U2 - 10.1172/JCI37581
DO - 10.1172/JCI37581
M3 - Article
C2 - 19855130
AN - SCOPUS:70449355084
SN - 0021-9738
VL - 119
SP - 3213
EP - 3225
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -