Proteinase 3 Induces Neuronal Cell Death Through Microglial Activation.
Proteinase 3 (PR3) is released from neutrophil granules and is involved in the inflammatory process. PR3 is implicated in antimicrobial defense and cell death, but the exact role of PR3 in the brain is less defined. Microglia is the major immune effector cells in the CNS and is activated by brain injury. In the present study, the effect of PR3 on glial activation was investigated. Microglial activation was assessed by the intracellular level of reactive oxygen species and expression of inflammatory cytokines. The conditioned media from activated microglia by PR3 was used for measuring the neurotoxic effects of PR3-stimulated microglia. The effects of PR3 in vivo were measured by microinjecting PR3 into the rat brain. Herein we show that PR3 increased the inflammatory responses including the intracellular ROS and pro-inflammatory cytokine production in rat primary microglia. Conditioned media from PR3-treated microglia induced neuronal cell death in a concentration dependent manner. Furthermore, microinjected PR3 into the striatum of the rat brain induced microglial activation and neuronal cell death. Interestingly treatment with anti-PR3 monoclonal antibody and protease inhibitors ameliorated microglial activation induced by PR3 in primary microglia and striatum, which also prevented neuronal cell death in both conditions. The data presented here suggest that PR3 is a direct modulator of microglial activation and causes neuronal death through the augmentation of inflammatory responses. We suggest that PR3 could be a new modulator of neuroinflammation, and blocking PR3 would be a promising novel therapeutic target for neuroinflammatory disease such as stroke and Alzheimer's disease.
Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
Kyu Suk
KS
Cho
Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
Eun Joo
EJ
Lee
Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
Jung Nam
JN
Kim
Department of Pharmacology, College of Pharmacy, Gachon University, Incheon, Korea.
Ji Woong
JW
Choi
Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.|Department of Neurology, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Seoul, Korea.
Hahn Young
HY
Kim
Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.|Department of Neurology, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Seoul, Korea.
Seol-Heui
SH
Han
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
Jong Hoon
JH
Ryu
Department of Pharmacy, College of Pharmacy, Sahmyook University, Seoul, Korea.
Jae Hoon
JH
Cheong
Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea.
Chan Young
CY
Shin
Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea. neuro11@kku.ac.kr.
Kyoung Ja
KJ
Kwon
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002540:Cerebral Cortex / Q000473:pathology; D003342:Corpus Striatum / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D017628:Microglia / Q000187:drug effects*; D008845:Microinjections; D053146:Myeloblastin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D016207:Cytokines; D017382:Reactive Oxygen Species; D053146:Myeloblastin
Glial activation; Neuroinflammation; Neuronal death; PR3; ROS