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J Biol Chem. 2016 Sep 2;291(36):18843-52. doi: 10.1074/jbc.M116.720870. Epub 2016 Jul 11.

Mice Deficient in Angiopoietin-like Protein 2 (Angptl2) Gene Show Increased Susceptibility to Bacterial Infection Due to Attenuated Macrophage Activity.

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From the Departments of Molecular Genetics, Orthopedic Surgery, and.
From the Departments of Molecular Genetics,
Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
From the Departments of Molecular Genetics.
Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan, and.
Orthopedic Surgery, and.
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


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.


Angptl2; cytokine induction; inflammation; innate immunity; macrophage; microbiology

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