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Kallikrein 12 Regulates Innate Resistance of Murine Macrophages against Mycobacterium bovis Infection by Modulating Autophagy and Apoptosis

Identifieur interne : 000704 ( Main/Exploration ); précédent : 000703; suivant : 000705

Kallikrein 12 Regulates Innate Resistance of Murine Macrophages against Mycobacterium bovis Infection by Modulating Autophagy and Apoptosis

Auteurs : Naveed Sabir ; Tariq Hussain ; Yi Liao ; Jie Wang ; Yinjuan Song ; Muhammad Shahid ; Guangyu Cheng ; Mazhar Hussain Mangi ; Jiao Yao ; Lifeng Yang ; Deming Zhao ; Xiangmei Zhou

Source :

RBID : PMC:6562459

Abstract

Mycobacterium bovis (M. bovis) is a member of the Mycobacterium tuberculosis (Mtb) complex causing bovine tuberculosis (TB) and imposing a high zoonotic threat to human health. Kallikreins (KLKs) belong to a subgroup of secreted serine proteases. As their role is established in various physiological and pathological processes, it is likely that KLKs expression may mediate a host immune response against the M. bovis infection. In the current study, we report in vivo and in vitro upregulation of KLK12 in the M. bovis infection. To define the role of KLK12 in immune response regulation of murine macrophages, we produced KLK12 knockdown bone marrow derived macrophages (BMDMs) by using siRNA transfection. Interestingly, the knockdown of KLK12 resulted in a significant downregulation of autophagy and apoptosis in M. bovis infected BMDMs. Furthermore, we demonstrated that this KLK12 mediated regulation of autophagy and apoptosis involves mTOR/AMPK/TSC2 and BAX/Bcl-2/Cytochrome c/Caspase 3 pathways, respectively. Similarly, inflammatory cytokines IL-1β, IL-6, IL-12 and TNF-α were significantly downregulated in KLK12 knockdown macrophages but the difference in IL-10 and IFN-β expression was non-significant. Taken together, these findings suggest that upregulation of KLK12 in M. bovis infected murine macrophages plays a substantial role in the protective immune response regulation by modulating autophagy, apoptosis and pro-inflammatory pathways. To our knowledge, this is the first report on expression and the role of KLK12 in the M. bovis infection and the data may contribute to a new paradigm for diagnosis and treatment of bovine TB.


Url:
DOI: 10.3390/cells8050415
PubMed: 31060300
PubMed Central: 6562459


Affiliations:


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Le document en format XML

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<name sortKey="Liao, Yi" sort="Liao, Yi" uniqKey="Liao Y" first="Yi" last="Liao">Yi Liao</name>
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<name sortKey="Wang, Jie" sort="Wang, Jie" uniqKey="Wang J" first="Jie" last="Wang">Jie Wang</name>
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<name sortKey="Song, Yinjuan" sort="Song, Yinjuan" uniqKey="Song Y" first="Yinjuan" last="Song">Yinjuan Song</name>
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<nlm:aff id="af2-cells-08-00415">Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
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<name sortKey="Cheng, Guangyu" sort="Cheng, Guangyu" uniqKey="Cheng G" first="Guangyu" last="Cheng">Guangyu Cheng</name>
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<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
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<name sortKey="Mangi, Mazhar Hussain" sort="Mangi, Mazhar Hussain" uniqKey="Mangi M" first="Mazhar Hussain" last="Mangi">Mazhar Hussain Mangi</name>
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<name sortKey="Yao, Jiao" sort="Yao, Jiao" uniqKey="Yao J" first="Jiao" last="Yao">Jiao Yao</name>
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<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
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<author>
<name sortKey="Yang, Lifeng" sort="Yang, Lifeng" uniqKey="Yang L" first="Lifeng" last="Yang">Lifeng Yang</name>
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<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
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<name sortKey="Zhao, Deming" sort="Zhao, Deming" uniqKey="Zhao D" first="Deming" last="Zhao">Deming Zhao</name>
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<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
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<name sortKey="Zhou, Xiangmei" sort="Zhou, Xiangmei" uniqKey="Zhou X" first="Xiangmei" last="Zhou">Xiangmei Zhou</name>
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<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
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<title xml:lang="en" level="a" type="main">Kallikrein 12 Regulates Innate Resistance of Murine Macrophages against
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Infection by Modulating Autophagy and Apoptosis</title>
<author>
<name sortKey="Sabir, Naveed" sort="Sabir, Naveed" uniqKey="Sabir N" first="Naveed" last="Sabir">Naveed Sabir</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
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(J.W.);
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(Y.S.);
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(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
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(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hussain, Tariq" sort="Hussain, Tariq" uniqKey="Hussain T" first="Tariq" last="Hussain">Tariq Hussain</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
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(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
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(J.W.);
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(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
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(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Liao, Yi" sort="Liao, Yi" uniqKey="Liao Y" first="Yi" last="Liao">Yi Liao</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
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(J.W.);
<email>syinjuan@126.com</email>
(Y.S.);
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(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wang, Jie" sort="Wang, Jie" uniqKey="Wang J" first="Jie" last="Wang">Jie Wang</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
<email>wangjie1985abc@163.com</email>
(J.W.);
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(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
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(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
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(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Song, Yinjuan" sort="Song, Yinjuan" uniqKey="Song Y" first="Yinjuan" last="Song">Yinjuan Song</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
<email>wangjie1985abc@163.com</email>
(J.W.);
<email>syinjuan@126.com</email>
(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Shahid, Muhammad" sort="Shahid, Muhammad" uniqKey="Shahid M" first="Muhammad" last="Shahid">Muhammad Shahid</name>
<affiliation>
<nlm:aff id="af2-cells-08-00415">Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>drshahid_vet@yahoo.com</email>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cheng, Guangyu" sort="Cheng, Guangyu" uniqKey="Cheng G" first="Guangyu" last="Cheng">Guangyu Cheng</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
<email>wangjie1985abc@163.com</email>
(J.W.);
<email>syinjuan@126.com</email>
(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
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</author>
<author>
<name sortKey="Mangi, Mazhar Hussain" sort="Mangi, Mazhar Hussain" uniqKey="Mangi M" first="Mazhar Hussain" last="Mangi">Mazhar Hussain Mangi</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
<email>wangjie1985abc@163.com</email>
(J.W.);
<email>syinjuan@126.com</email>
(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Yao, Jiao" sort="Yao, Jiao" uniqKey="Yao J" first="Jiao" last="Yao">Jiao Yao</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
<email>wangjie1985abc@163.com</email>
(J.W.);
<email>syinjuan@126.com</email>
(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Yang, Lifeng" sort="Yang, Lifeng" uniqKey="Yang L" first="Lifeng" last="Yang">Lifeng Yang</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
<email>wangjie1985abc@163.com</email>
(J.W.);
<email>syinjuan@126.com</email>
(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Zhao, Deming" sort="Zhao, Deming" uniqKey="Zhao D" first="Deming" last="Zhao">Deming Zhao</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
<email>wangjie1985abc@163.com</email>
(J.W.);
<email>syinjuan@126.com</email>
(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Zhou, Xiangmei" sort="Zhou, Xiangmei" uniqKey="Zhou X" first="Xiangmei" last="Zhou">Xiangmei Zhou</name>
<affiliation>
<nlm:aff id="af1-cells-08-00415">Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
<email>naveedsabir@upr.edu.pk</email>
(N.S.);
<email>drtariq@aup.edu.pk</email>
(T.H.);
<email>liaoyi_cau@126.com</email>
(Y.L.);
<email>wangjie1985abc@163.com</email>
(J.W.);
<email>syinjuan@126.com</email>
(Y.S.);
<email>hnchdd@163.com</email>
(G.C.);
<email>drmazharmangi114@gmail.com</email>
(M.H.M.);
<email>mole-yao@hotmail.com</email>
(J.Y.);
<email>yanglf@cau.edu.cn</email>
(L.Y.);
<email>zhaodm@cau.edu.cn</email>
(D.Z.)</nlm:aff>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Cells</title>
<idno type="eISSN">2073-4409</idno>
<imprint>
<date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>
<italic>Mycobacterium bovis</italic>
(
<italic>M. bovis</italic>
) is a member of the
<italic>Mycobacterium tuberculosis</italic>
(
<italic>Mtb</italic>
) complex causing bovine tuberculosis (TB) and imposing a high zoonotic threat to human health. Kallikreins (KLKs) belong to a subgroup of secreted serine proteases. As their role is established in various physiological and pathological processes, it is likely that KLKs expression may mediate a host immune response against the
<italic>M. bovis</italic>
infection. In the current study, we report in vivo and in vitro upregulation of KLK12 in the
<italic>M. bovis</italic>
infection. To define the role of KLK12 in immune response regulation of murine macrophages, we produced KLK12 knockdown bone marrow derived macrophages (BMDMs) by using siRNA transfection. Interestingly, the knockdown of KLK12 resulted in a significant downregulation of autophagy and apoptosis in
<italic>M. bovis</italic>
infected BMDMs. Furthermore, we demonstrated that this KLK12 mediated regulation of autophagy and apoptosis involves mTOR/AMPK/TSC2 and BAX/Bcl-2/Cytochrome c/Caspase 3 pathways, respectively. Similarly, inflammatory cytokines IL-1β, IL-6, IL-12 and TNF-α were significantly downregulated in KLK12 knockdown macrophages but the difference in IL-10 and IFN-β expression was non-significant. Taken together, these findings suggest that upregulation of KLK12 in
<italic>M. bovis</italic>
infected murine macrophages plays a substantial role in the protective immune response regulation by modulating autophagy, apoptosis and pro-inflammatory pathways. To our knowledge, this is the first report on expression and the role of KLK12 in the
<italic>M. bovis</italic>
infection and the data may contribute to a new paradigm for diagnosis and treatment of bovine TB.</p>
</div>
</front>
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</record>

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