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L-Amino acid oxidase plays a crucial role in host defense in the mammary glands

Kentaro Nagaoka^*,1, Fugaku Aoki, Mizuna Hayashi^*, Yoshikage Muroi^*, Toshihiro Sakurai^*, Kikuji Itoh, Masahito Ikawa, Masaru Okabe, Kazuhiko Imakawa^* and Senkiti Sakai^*

^* Laboratory of Animal Breeding and

Laboratory of Veterinary Public Health, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan;

Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan; and

Genome Information Research Center, Osaka University, Osaka, Japan

¹ Correspondence: Laboratory of Animal Breeding, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. E-mail: akenaga{at}mail.ecc.u-tokyo.ac.jp

The innate immune system plays an important role in protecting organs that are continuous with the outer surface of the body from bacterial infection. The antibacterial factors involved in this system have been sought in exocrine glands, particularly in the mammary glands. Because milk produced in the mammary glands is enriched in various nutrients, supporting the proliferation of bacteria, mammary glands appear to be at the greatest risk of bacterial infection and proliferation. Here, we show that mouse milk contains L-amino acid oxidase (LAO), a lactating mammary gland-specific protein that displays antibacterial activity in vitro through the production of hydrogen peroxide from free amino acids. We produced LAO-disrupted mouse lines to define the physiological properties and importance of the protein in vivo. The LAO-knockout mice were healthy and had normal mammary gland development; however, the antibacterial activity normally observed in milk from wild-type mice was absent from the milk of knockout mice. The content of free amino acids targeted by LAO was very low in wild-type milk, whereas these amino acids were abundant in LAO-knockout milk. Knockout mice exhibited weak resistance to an intramammary bacterial challenge compared to their wild-type counterparts. Further, preadministration of wild-type milk whey reduced the severity of bacterial infection in LAO-knockout mice. These results demonstrate that milk LAO protects the mammary gland against bacterial infection, and this antibacterial effect may be due to the generation of hydrogen peroxide by using free amino acids abundantly present in milk. Nagaoka, K., Aoki, F., Hayashi, M., Muroi, Y., Sakurai, T., Itoh, K., Ikawa, M., Okabe, M., Imakawa, K., Sakai, S. L-Amino acid oxidase plays a crucial role in host defense in the mammary glands.

Key Words: antibacterial • milk • H₂O₂ • mastitis