title: Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum.
abstract: 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 (CflarHep-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. CflarHep-lowmice 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 CflarHep-lowmice. 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 CflarHep-lowmice. We reconstituted CflarHep-lowmice 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 CflarHep-lowmice pretreated with diphtheria toxin, whereas KCs remained present in the livers. Under these experimental conditions, LysM-DTR BM-reconstituted CflarHep-lowmice 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, CflarHep-lowmice following TNFα injection.
  
  
  
  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).
authors: Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
authors: Xuehua
authors: X
authors: Piao
authors: Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
authors: Soh
authors: S
authors: Yamazaki
authors: Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
authors: Sachiko
authors: S
authors: Komazawa-Sakon
authors: Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
authors: Sanae
authors: S
authors: Miyake
authors: Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
authors: Osamu
authors: O
authors: Nakabayashi
authors: Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
authors: Takeyuki
authors: T
authors: Kurosawa
authors: Department of Pathology, Toho University School of Medicine, Tokyo, Japan.
authors: Tetsuo
authors: T
authors: Mikami
authors: Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Minoru
authors: M
authors: Tanaka
authors: Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam, Netherlands.
authors: Nico
authors: N
authors: Van Rooijen
authors: Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan.
authors: Masaki
authors: M
authors: Ohmuraya
authors: RIKEN Center for Sustainable Resource Science, Yokohama, Japan.|Faculty of Agriculture, Yamagata University, Yamagata, Japan.
authors: Akira
authors: A
authors: Oikawa
authors: Laboratory of Biomedical Imaging Research, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors: Yuko
authors: Y
authors: Kojima
authors: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors: Soichiro
authors: S
authors: Kakuta
authors: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors: Yasuo
authors: Y
authors: Uchiyama
authors: Laboratory of Immune regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors: Masato
authors: M
authors: Tanaka
authors: Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
authors: Hiroyasu
authors: H
authors: Nakano
mesh_terms: D000818:Animals; D017209:Apoptosis; D018450:Disease Progression; D006505:Hepatitis / Q000097:blood* / Q000209:etiology*; D022781:Hepatocytes; D006657:Histones / Q000097:blood*; D007728:Kupffer Cells; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D006657:Histones; D014409:Tumor Necrosis Factor-alpha