PMID- 27756321 OWN - NLM STAT- MEDLINE DCOM- 20171005 LR - 20181202 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 13 IP - 1 DP - 2016 Oct 19 TI - EGFR transactivation contributes to neuroinflammation in Streptococcus suis meningitis. PG - 274 LID - 274 AB - BACKGROUND: Streptococcus suis serotype 2 (SS2) is an important zoonotic bacterial pathogen in both humans and animals, which can cause high morbidity and mortality. Meningitis is one of the major clinical manifestations of SS2 infection. However, the specific process of SS2 meningitis and its molecular mechanisms remain unclear. Epidermal growth factor receptor (EGFR) has been reported to initiate transduction of intracellular signals and regulate host inflammatory responses. Whether and how EGFR contributes to the development of S. suis meningitis are currently unknown. METHODS: The tyrosine phosphorylation of cellular proteins, the transactivation of EGFR, as well as its dimerization, and the associated signal transduction pathways were investigated by immunoprecipitation and western blotting. Real-time quantitative PCR was used to investigate the transcriptional level of the ErbB family members, EGFR-related ligands, cytokines, and chemokines. The secretion of cytokines and chemokines in the serum and brain were detected by Q-Plex Chemiluminescent ELISA. RESULTS: We found an important role of EGFR in SS2 strain SC19-induced meningitis. SC19 increasingly adhered to human brain microvascular endothelial cells (hBMEC) and caused inflammatory lesions in the brain tissues, with significant induction and secretion of proinflammatory cytokines and chemokines in the serum and brains. SC19 infection of hBMEC induced tyrosine phosphorylation of cellular EGFR in a ligand-dependent manner involving the EGF-like ligand HB-EGF, amphiregulin (AREG), and epiregulin (EREG) and led to heterodimerization of EGFR/ErbB3. The EGFR transactivation did not participate in SS2 strain SC19 adhesion of hBMEC, as well as in bacterial colonization in vivo. However, its transactivation contributed to the bacterial-induced neuroinflammation, via triggering the MAPK-ERK1/2 and NF-kappaB signaling pathways in hBMEC that promote the production of proinflammatory cytokines and chemokines. CONCLUSIONS: We investigated for the first time the tyrosine phosphorylation of cellular proteins in response to SS2 strain SC19 infection of hBMEC and demonstrated the contribution of EGFR to SS2-induced neuroinflammation. These observations propose a novel mechanism involving EGFR in SS2-mediated inflammatory responses in the brain, and therefore, EGFR might be an important host target for further investigation and prevention of neuroinflammation caused by SS2 strains. FAU - Yang, Xiao-Pei AU - Yang XP AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Fu, Ji-Yang AU - Fu JY AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Yang, Rui-Cheng AU - Yang RC AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Liu, Wen-Tong AU - Liu WT AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Zhang, Tao AU - Zhang T AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Yang, Bo AU - Yang B AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Miao, Ling AU - Miao L AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Dou, Bei-Bei AU - Dou BB AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Tan, Chen AU - Tan C AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - Key Laboratory of Development of Veterinary Diagnostic Products of Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Chen, Huan-Chun AU - Chen HC AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. AD - Key Laboratory of Development of Veterinary Diagnostic Products of Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. FAU - Wang, Xiang-Ru AU - Wang XR AD - State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. wangxr228@mail.hzau.edu.cn. AD - The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. wangxr228@mail.hzau.edu.cn. AD - Key Laboratory of Development of Veterinary Diagnostic Products of Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. wangxr228@mail.hzau.edu.cn. LA - eng PT - Journal Article DEP - 20161019 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Amphiregulin) RN - 0 (Cytokines) RN - 0 (Enzyme Inhibitors) RN - 0 (Quinazolines) RN - 0 (Tyrphostins) RN - 170449-18-0 (RTKI cpd) RN - 42HK56048U (Tyrosine) RN - EC 2.7.10.1 (EGFR protein, mouse) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (ErbB3 protein, mouse) RN - EC 2.7.10.1 (Receptor, ErbB-3) SB - IM MH - Amphiregulin/metabolism MH - Animals MH - Brain/*metabolism/microbiology/pathology MH - Cytokines/genetics/metabolism MH - Endothelial Cells/drug effects/metabolism MH - Enzyme Inhibitors/pharmacology MH - ErbB Receptors/genetics/*metabolism MH - Female MH - Humans MH - *Meningitis/etiology/microbiology/physiopathology MH - Mice MH - Phosphorylation/drug effects MH - Quinazolines/pharmacology MH - Receptor, ErbB-3/metabolism MH - Signal Transduction/drug effects/physiology MH - Streptococcal Infections/*complications/microbiology/*physiopathology MH - Streptococcus suis/*physiology MH - Swine MH - Transcriptional Activation/*physiology MH - Tyrosine/metabolism MH - Tyrphostins/pharmacology PMC - PMC5070219 OTO - NOTNLM OT - Brain microvascular endothelial cell OT - EGFR OT - Neuroinflammation OT - Streptococcus suis EDAT- 2016/10/21 06:00 MHDA- 2017/10/06 06:00 PMCR- 2016/10/19 CRDT- 2016/10/21 06:00 PHST- 2016/07/31 00:00 [received] PHST- 2016/09/26 00:00 [accepted] PHST- 2016/10/21 06:00 [pubmed] PHST- 2017/10/06 06:00 [medline] PHST- 2016/10/21 06:00 [entrez] PHST- 2016/10/19 00:00 [pmc-release] AID - 10.1186/s12974-016-0734-0 [pii] AID - 734 [pii] AID - 10.1186/s12974-016-0734-0 [doi] PST - epublish SO - J Neuroinflammation. 2016 Oct 19;13(1):274. doi: 10.1186/s12974-016-0734-0.