PMID- 28743960 OWN - NLM STAT- MEDLINE DCOM- 20190227 LR - 20190227 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 7 IP - 1 DP - 2017 Jul 25 TI - NADPH oxidase 4 is required for the generation of macrophage migration inhibitory factor and host defense against Toxoplasma gondii infection. PG - 6361 LID - 10.1038/s41598-017-06610-4 [doi] LID - 6361 AB - 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-kappaB 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. FAU - Kim, Ji Hye AU - Kim JH AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Lee, Jina AU - Lee J AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Bae, Su-Jin AU - Bae SJ AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Kim, Yeeun AU - Kim Y AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Park, Byung-Joon AU - Park BJ AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Choi, Jae-Won AU - Choi JW AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Kwon, Jaeyul AU - Kwon J AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. AD - Department of Medical Education, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Cha, Guang-Ho AU - Cha GH AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Yoo, Heon Jong AU - Yoo HJ AD - Department of Obstetrics and Gynecology, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Jo, Eun-Kyeong AU - Jo EK AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. AD - Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea. FAU - Bae, Yun Soo AU - Bae YS AD - Department of Life Science, Ewha Womans University, Seoul, South Korea. FAU - Lee, Young-Ha AU - Lee YH AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. yhalee@cnu.ac.kr. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. yhalee@cnu.ac.kr. FAU - Yuk, Jae-Min AU - Yuk JM AUID- ORCID: 0000-0002-0630-9194 AD - Department of Infection Biology, College of Medicine, Chungnam National University, Daejeon, South Korea. yjaemin0@cnu.ac.kr. AD - Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. yjaemin0@cnu.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170725 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Macrophage Migration-Inhibitory Factors) RN - 0 (NF-kappa B) RN - 0 (Reactive Oxygen Species) RN - EC 1.6.3.- (NADPH Oxidase 4) RN - EC 1.6.3.- (Nox4 protein, mouse) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 5.3.- (Intramolecular Oxidoreductases) RN - EC 5.3.2.1 (Mif protein, mouse) SB - IM MH - Animals MH - Cell Line MH - Disease Models, Animal MH - *Disease Resistance MH - Gene Knockdown Techniques MH - Humans MH - Immunity, Innate MH - Intramolecular Oxidoreductases/genetics/*metabolism MH - Macrophage Migration-Inhibitory Factors/genetics/*metabolism MH - Macrophages/cytology/metabolism/parasitology MH - Mice MH - Mitogen-Activated Protein Kinases/metabolism MH - NADPH Oxidase 4/*genetics MH - NF-kappa B/metabolism MH - RAW 264.7 Cells MH - Reactive Oxygen Species/metabolism MH - Toxoplasma/*immunology MH - Toxoplasmosis/genetics/*immunology/metabolism MH - Up-Regulation PMC - PMC5526938 COIS- The authors declare that they have no competing interests. EDAT- 2017/07/27 06:00 MHDA- 2019/02/28 06:00 PMCR- 2017/07/25 CRDT- 2017/07/27 06:00 PHST- 2017/01/13 00:00 [received] PHST- 2017/06/14 00:00 [accepted] PHST- 2017/07/27 06:00 [entrez] PHST- 2017/07/27 06:00 [pubmed] PHST- 2019/02/28 06:00 [medline] PHST- 2017/07/25 00:00 [pmc-release] AID - 10.1038/s41598-017-06610-4 [pii] AID - 6610 [pii] AID - 10.1038/s41598-017-06610-4 [doi] PST - epublish SO - Sci Rep. 2017 Jul 25;7(1):6361. doi: 10.1038/s41598-017-06610-4.