Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 51; pp. 20699 - 20704
• Main Authors: Yanai, Hideyuki, Matsuda, Atsushi, An, Jianbo, Koshiba, Ryuji, Nishio, Junko, Negishi, Hideo, Ikushima, Hiroaki, Onoe, Takashi, Ohdan, Hideki, Yoshida, Nobuaki, Taniguchi, Tadatsugu
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.12.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Animals; Apoptosis; Autophagy - genetics; Autophagy - immunology; B lymphocytes; Bacteria; Bacterial infections; Bacterial proteins; Binding sites; Biochemistry; Biological Sciences; Cell death; Cell Line; Cell lines; Endotoxemia; Endotoxemia - genetics; Endotoxemia - immunology; Endotoxemia - metabolism; Endotoxemia - pathology; Gene Deletion; Gene expression regulation; HMGB1 Protein - genetics; HMGB1 Protein - immunology; HMGB1 Protein - metabolism; Immunity, Innate; Infections; Listeria; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeriosis - genetics; Listeriosis - immunology; Listeriosis - metabolism; Listeriosis - pathology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Mice; Mice, Transgenic; Myeloid cells; Pathology; Rodents; IL-1β; IL-18; LPS
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1320808110

High-mobility group box 1 (HMGB1) is a DNA-binding protein abundantly expressed in the nucleus that has gained much attention for its regulation of immunity and inflammation. Despite this, whether and how HMGB1 contributes to protective and/or pathological responses in vivo is unclear. In this study, we constructed Hmgb1 -floxed (Hmgb1 ᶠ/ᶠ) mice to achieve the conditional inactivation of the gene in a cell- and tissue-specific manner by crossing these mice with an appropriate Cre recombinase transgenic strain. Interestingly, although mice with HMGB1 ablation in myeloid cells apparently develop normally, they are more sensitive to endotoxin shock compared with control mice, which is accompanied by massive macrophage cell death. Furthermore, these mice also show an increased sensitivity to Listeria monocytogenes infection. We also provide evidence that the loss of HMGB1 in macrophages results in the suppression of autophagy, which is commonly induced by lipopolysaccharide stimulation or L. monocytogenes infection. Thus, intracellular HMGB1 contributes to the protection of mice from endotoxemia and bacterial infection by mediating autophagy in macrophages. These newly generated HMGB1 conditional knockout mice will serve a useful tool with which to study further the in vivo role of this protein in various pathological conditions.