PMID- 31060300 OWN - NLM STAT- MEDLINE DCOM- 20191219 LR - 20200309 IS - 2073-4409 (Print) IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 8 IP - 5 DP - 2019 May 5 TI - Kallikrein 12 Regulates Innate Resistance of Murine Macrophages against Mycobacterium bovis Infection by Modulating Autophagy and Apoptosis. LID - 10.3390/cells8050415 [doi] LID - 415 AB - 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-1beta, IL-6, IL-12 and TNF-alpha were significantly downregulated in KLK12 knockdown macrophages but the difference in IL-10 and IFN-beta 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. FAU - Sabir, Naveed AU - Sabir N AD - 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. naveedsabir@upr.edu.pk. FAU - Hussain, Tariq AU - Hussain T AD - 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. drtariq@aup.edu.pk. FAU - Liao, Yi AU - Liao Y AD - 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. liaoyi_cau@126.com. FAU - Wang, Jie AU - Wang J AD - 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. wangjie1985abc@163.com. FAU - Song, Yinjuan AU - Song Y AD - 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. syinjuan@126.com. FAU - Shahid, Muhammad AU - Shahid M AD - Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. drshahid_vet@yahoo.com. FAU - Cheng, Guangyu AU - Cheng G AD - 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. hnchdd@163.com. FAU - Mangi, Mazhar Hussain AU - Mangi MH AD - 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. drmazharmangi114@gmail.com. FAU - Yao, Jiao AU - Yao J AD - 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. mole-yao@hotmail.com. FAU - Yang, Lifeng AU - Yang L AD - 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. yanglf@cau.edu.cn. FAU - Zhao, Deming AU - Zhao D AD - 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. zhaodm@cau.edu.cn. FAU - Zhou, Xiangmei AU - Zhou X AUID- ORCID: 0000-0003-1566-5745 AD - 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. zhouxm@cau.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190505 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Cytokines) RN - EC 3.4.21.- (Kallikreins) SB - IM MH - Animals MH - *Apoptosis MH - *Autophagy MH - Cattle MH - Cytokines/metabolism MH - *Immunity, Innate MH - Kallikreins/*metabolism MH - Macrophages/microbiology/*pathology MH - Mice MH - Mice, Inbred C57BL MH - Microbial Viability MH - Mycobacterium bovis/*physiology MH - RAW 264.7 Cells MH - Signal Transduction MH - Tuberculosis, Bovine/*immunology/*microbiology/pathology PMC - PMC6562459 OTO - NOTNLM OT - Kallikrein12 OT - Mycobacterium bovis OT - apoptosis OT - autophagy OT - cytokines OT - murine macrophages COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2019/05/08 06:00 MHDA- 2019/05/08 06:01 PMCR- 2019/05/01 CRDT- 2019/05/08 06:00 PHST- 2019/03/18 00:00 [received] PHST- 2019/04/29 00:00 [revised] PHST- 2019/04/30 00:00 [accepted] PHST- 2019/05/08 06:00 [entrez] PHST- 2019/05/08 06:00 [pubmed] PHST- 2019/05/08 06:01 [medline] PHST- 2019/05/01 00:00 [pmc-release] AID - cells8050415 [pii] AID - cells-08-00415 [pii] AID - 10.3390/cells8050415 [doi] PST - epublish SO - Cells. 2019 May 5;8(5):415. doi: 10.3390/cells8050415.