title: Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death.
abstract: High mobility group box 1 (HMGB1), histone, and DNA are essential nuclear components involved in the regulation of chromosome structure and function. In addition to their nuclear function, these molecules act as damage-associated molecular patterns (DAMPs) alone or together when released extracellularly. The synergistic effect of these nuclear DNA-HMGB1-histone complexes as DAMP complexes (nDCs) on immune cells remains largely unexplored. Here, we demonstrate that nDCs limit survival of macrophages (e.g., RAW264.7 and peritoneal macrophages) but not cancer cells (e.g., HCT116, HepG2 and Hepa1-6). nDCs promote production of inflammatory tumor necrosis factor α (TNFα) release, triggering reactive oxygen species-dependent apoptosis and necrosis. Moreover, the receptor for advanced glycation end products (RAGE), but not toll-like receptor (TLR)-4 and TLR-2, was required for Akt-dependent TNFα release and subsequent cell death following treatment with nDCs. Genetic depletion of RAGE by RNAi, antioxidant N-Acetyl-l-cysteine, and TNFα neutralizing antibody significantly attenuated nDC-induced cell death. These findings provide evidence supporting novel signaling mechanisms linking nDCs and inflammation in macrophage cell death.
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Ruochan
authors: R
authors: Chen
authors: Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Sha
authors: S
authors: Fu
authors: Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Xue-Gong
authors: XG
authors: Fan
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Michael T
authors: MT
authors: Lotze
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Herbert J
authors: HJ
authors: Zeh
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: tangd2@upmc.edu.
authors: Daolin
authors: D
authors: Tang
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: kangr@upmc.edu.
authors: Rui
authors: R
authors: Kang
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004247:DNA / Q000276:immunology; D024243:HMGB1 Protein / Q000276:immunology*; D006657:Histones / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D024243:HMGB1 Protein; D006657:Histones; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; DNA; HMGB1; Histone; RAGE; TNFα