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Sci Rep. 2017 Jul 25;7(1):6361. doi: 10.1038/s41598-017-06610-4.

NADPH oxidase 4 is required for the generation of macrophage migration inhibitory factor and host defense against Toxoplasma gondii infection.

Kim JH1,2, Lee J1,2, Bae SJ1,2, Kim Y1, Park BJ1,2, Choi JW1,2, Kwon J2,3, Cha GH1,2, Yoo HJ4, Jo EK2,5, Bae YS6, Lee YH7,8, Yuk JM9,10.

Author information

1
Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea.
2
Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea.
3
Department of Medical Education, College of Medicine, Chungnam National University, Daejeon, South Korea.
4
Department of Obstetrics and Gynecology, College of Medicine, Chungnam National University, Daejeon, South Korea.
5
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
6
Department of Life Science, Ewha Womans University, Seoul, South Korea.
7
Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. yhalee@cnu.ac.kr.
8
Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. yhalee@cnu.ac.kr.
9
Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. yjaemin0@cnu.ac.kr.
10
Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. yjaemin0@cnu.ac.kr.

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) are an important family of catalytic enzymes that generate reactive oxygen species (ROS), which mediate the regulation of diverse cellular functions. Although phagocyte Nox2/gp91phox is closely associated with the activation of host innate immune responses, the roles of Nox family protein during Toxoplasma gondii (T. gondii) infection have not been fully investigated. Here, we found that T. gondii-mediated ROS production was required for the upregulation of macrophage migration inhibitory factor (MIF) mRNA and protein levels via activation of mitogen-activated protein kinase and nuclear factor-κB signaling in macrophages. Interestingly, MIF knockdown led to a significant increase in the survival of intracellular T. gondii in bone marrow-derived macrophages (BMDMs). Moreover, Nox4 deficiency, but not Nox2/gp91phox and the cytosolic subunit p47phox, resulted in enhanced survival of the intracellular T. gondii RH strain and impaired expression of T. gondii-mediated MIF in BMDMs. Additionally, Nox4-deficient mice showed increased susceptibility to virulent RH strain infection and increased cyst burden in brain tissues and low levels of MIF expression following infection with the avirulent ME49 strain. Collectively, our findings indicate that Nox4-mediated ROS generation plays a central role in MIF production and resistance to T. gondii infection.

PMID:
28743960
PMCID:
PMC5526938
DOI:
10.1038/s41598-017-06610-4
[Indexed for MEDLINE]
Free PMC Article

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