Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum

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• 作者：Xuehua Piao ; Soh Yamazaki ; Sachiko Komazawa‐Sakon ; Sanae Miyake ; Osamu Nakabayashi ; Takeyuki Kurosawa ; Tetsuo Mikami ; Minoru Tanaka ; Nico Van Rooijen ; Masaki Ohmuraya ; et al
• 刊名：Hepatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：65
• 期：1
• 页码：237-252
• 全文大小：2.0MB
• ISSN：1527-3350

文摘

Tissue-resident macrophages and bone marrow (BM)-derived monocytes play a crucial role in the maintenance of tissue homeostasis; however, their contribution to recovery from acute tissue injury is not fully understood. To address this issue, we generated an acute murine liver injury model using hepatocyte-specific Cflar-deficient (Cflar^Hep-low) mice. Cellular FLICE-inhibitory protein expression was down-regulated in Cflar-deficient hepatocytes, which thereby increased susceptibility of hepatocytes to death receptor–induced apoptosis. Cflar^Hep-low mice developed acute hepatitis and recovered with clearance of apoptotic hepatocytes at 24 hours after injection of low doses of tumor necrosis factor α (TNFα), which could not induce hepatitis in wild-type (WT) mice. Depletion of Kupffer cells (KCs) by clodronate liposomes did not impair clearance of dying hepatocytes or exacerbate hepatitis in Cflar^Hep-low mice. To elucidate the roles of BM-derived monocytes and neutrophils in clearance of apoptotic hepatocytes, we examined the effect of depletion of these cells on TNFα-induced hepatitis in Cflar^Hep-low mice. We reconstituted Cflar^Hep-low mice with BM cells from transgenic mice in which human diphtheria toxin receptor (DTR) was expressed under control of the lysozyme M (LysM) promoter. TNFα-induced infiltration of myeloid cells, including monocytes and neutrophils, was completely ablated in LysM-DTR BM-reconstituted Cflar^Hep-low mice pretreated with diphtheria toxin, whereas KCs remained present in the livers. Under these experimental conditions, LysM-DTR BM-reconstituted Cflar^Hep-low mice rapidly developed severe hepatitis and succumbed within several hours of TNFα injection. We found that serum interleukin-6 (IL-6), TNFα, and histone H3 were aberrantly increased in LysM-DTR BM-reconstituted, but not in WT BM-reconstituted, Cflar^Hep-low mice following TNFα injection. Conclusion: These findings indicate an unexpected role of myeloid cells in decreasing serum IL-6, TNFα, and histone H3 levels via the suppression of TNFα-induced hepatocyte apoptosis. (Hepatology 2017;65:237-252).