title: Mice Deficient in Angiopoietin-like Protein 2 (Angptl2) Gene Show Increased Susceptibility to Bacterial Infection Due to Attenuated Macrophage Activity.
abstract: Macrophages play crucial roles in combatting infectious disease by promoting inflammation and phagocytosis. Angiopoietin-like protein 2 (ANGPTL2) is a secreted factor that induces tissue inflammation by attracting and activating macrophages to produce inflammatory cytokines in chronic inflammation-associated diseases such as obesity-associated metabolic syndrome, atherosclerosis, and rheumatoid arthritis. Here, we asked whether and how ANGPTL2 activates macrophages in the innate immune response. ANGPTL2 was predominantly expressed in proinflammatory mouse bone marrow-derived differentiated macrophages (GM-BMMs) following GM-CSF treatment relative to anti-inflammatory cells (M-BMMs) established by M-CSF treatment. Expression of the proinflammatory markers IL-1β, IL-12p35, and IL-12p40 significantly decreased in GM-BMMs from Angptl2-deficient compared with wild-type (WT) mice, suggestive of attenuated proinflammatory activity. We also report that ANGPTL2 inflammatory signaling is transduced through integrin α5β1 rather than through paired immunoglobulin-like receptor B. Interestingly, Angptl2-deficient mice were more susceptible to infection with Salmonella enterica serovar Typhimurium than were WT mice. Moreover, nitric oxide (NO) production by Angptl2-deficient GM-BMMs was significantly lower than in WT GM-BMMs. Collectively, our findings suggest that macrophage-derived ANGPTL2 promotes an innate immune response in those cells by enhancing proinflammatory activity and NO production required to fight infection.
authors.affiliation: From the Departments of Molecular Genetics, Orthopedic Surgery, and.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yugami
authors.affiliation: From the Departments of Molecular Genetics, Orthopedic Surgery, and.
authors.forename: Haruki
authors.initials: H
authors.lastname: Odagiri
authors.affiliation: From the Departments of Molecular Genetics, enmoto@gpo.kumamoto-u.ac.jp.
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.affiliation: Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Tsutsuki
authors.affiliation: Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Shigemoto
authors.initials: S
authors.lastname: Fujii
authors.affiliation: From the Departments of Molecular Genetics.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.affiliation: From the Departments of Molecular Genetics, Orthopedic Surgery, and.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Masuda
authors.affiliation: From the Departments of Molecular Genetics.
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: From the Departments of Molecular Genetics.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Terada
authors.affiliation: From the Departments of Molecular Genetics, Orthopedic Surgery, and.
authors.forename: Hironori
authors.initials: H
authors.lastname: Tanoue
authors.affiliation: From the Departments of Molecular Genetics, Orthopedic Surgery, and.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: From the Departments of Molecular Genetics.
authors.forename: Jun
authors.initials: J
authors.lastname: Morinaga
authors.affiliation: From the Departments of Molecular Genetics.
authors.forename: Haruki
authors.initials: H
authors.lastname: Horiguchi
authors.affiliation: From the Departments of Molecular Genetics.
authors.forename: Taichi
authors.initials: T
authors.lastname: Sugizaki
authors.affiliation: Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
authors.affiliation: From the Departments of Molecular Genetics.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Gotoh
authors.affiliation: Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan, and.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.affiliation: Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sawa
authors.affiliation: Orthopedic Surgery, and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuta
authors.affiliation: From the Departments of Molecular Genetics, Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo 102-0076, Japan oike@gpo.kumamoto-u.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000276:immunology*; D000818:Animals; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology*; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*
chemical_list: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D009569:Nitric Oxide
keywords: Angptl2; cytokine induction; inflammation; innate immunity; macrophage; microbiology