Contrasting responses of K upffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury

Abstract Background Biliary obstruction and cholestasis are serious complications of many liver diseases. Although resident hepatic macrophages ( K upffer cells) are frequently implicated in disease progression, most studies fail to differentiate the contribution of K upffer cells and inflammatory mononuclear phagocytes ( iMNP s) that infiltrate the liver subsequent to obstruction. Aim This study was undertaken to examine the roles and potential interactions of these two disparate mononuclear phagocyte populations in hepatic injury attending cholestasis. Methods Female, C57Bl/6 mice were injected with magnetic beads on day 3 prior to sham operation or bile duct ligation ( BDL ) to facilitate subsequent K upffer cell isolation. Three days post‐surgery, animals were euthanized, and bead‐containing K upffer cells and iMNP s were separated, purified and analysed. To examine the ability of K upffer cells to modulate iMNP activity, iMNP s were isolated from the livers of intact and K upffer cell‐depleted mice on day 3 post‐surgery and compared. Results Purified K upffer cells and iMNP populations obtained from BDL mice exhibited heterogeneous morphologies rendering them visually indistinguishable. iMNP s, however, were characterized by the increased expression of Ly‐6C and CD11b and the elevated production of chemokines/cytokines characteristic of inflammatory cells. In the absence of K upffer cells, iMNP s immigrating to the liver following BDL exhibited significant decreases in CD11b and Ly‐6C expression, and in pro‐inflammatory chemokine/cytokine production. Conclusions Kupffer cells and iMNP s exhibit disparate biological responses to biliary obstruction and cholestasis. K upffer cells play a key role in regulating iMNP influx and activity.