Cathepsin S contributes to microglia-mediated olfactory dysfunction through the regulation of Cx3cl1-Cx3cr1 axis in a Niemann-Pick disease type C1 model.
Microglia can aggravate olfactory dysfunction by mediating neuronal death in the olfactory bulb (OB) of a murine model of Niemann-Pick disease type C1 (NPC1), a fatal neurodegenerative disorder accompanied by lipid trafficking defects. In this study, we focused on the crosstalk between neurons and microglia to elucidate the mechanisms underlying extensive microgliosis in the NPC1-affected brain. Microglia in the OB of NPC1 mice strongly expressed CX3C chemokine receptor 1 (Cx3cr1), a specific receptor for the neural chemokine C-X3-C motif ligand 1 (Cx3cl1). In addition, a high level of Cx3cl1 was detected in NPC1 mouse-derived CSF due to enhanced catalytic activity of Cathepsin S (Ctss), which is responsible for Cx3cl1 secretion. Notably, nasal delivery of Cx3cl1 neutralizing antibody or Ctss inhibitor could inhibit the Cx3cl1-Cx3cr1 interaction and support neuronal survival through the suppression of microglial activation, leading to an improvement in the olfactory function in NPC1 mice. Relevant in vitro experiments revealed that intracellular cholesterol accumulation could act as a strong inducer of abnormal Ctss activation and, in turn, stimulated the Cx3cl1-Cx3cr1 axis in microglia via p38 mitogen-activated protein kinase signaling. Our data address the significance of Cx3cl1-Cx3cr1 interaction in the development of microglial neurotoxicity and suggest that Ctss is a key upstream regulator. Therefore, this study contributes to a better understanding of the crosstalk between neurons and microglia in the development of the neurodegeneration and provides a new perspective for the management of olfactory deficits and other microglia-dependent neuropathies. GLIA 2016;64:2291-2305.
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|School of Medicine, Pusan National University, Busan, 49241, South Korea.|Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, South Korea.
Yoojin
Y
Seo
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|School of Medicine, Pusan National University, Busan, 49241, South Korea.|Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, South Korea.
Hyung-Sik
HS
Kim
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
Insung
I
Kang
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
Soon Won
SW
Choi
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
Tae-Hoon
TH
Shin
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
Ji-Hee
JH
Shin
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
Byung-Chul
BC
Lee
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
Jin Young
JY
Lee
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
Jae-Jun
JJ
Kim
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
Myung Geun
MG
Kook
Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea. kangpub@snu.ac.kr.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea. kangpub@snu.ac.kr.
Kyung-Sun
KS
Kang
D000818:Animals; D000073883:CX3C Chemokine Receptor 1 / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005247:Feeding Behavior; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism*; D000077296:Niemann-Pick C1 Protein; D052536:Niemann-Pick Disease, Type A / Q000150:complications* / Q000235:genetics; D000857:Olfaction Disorders / Q000209:etiology* / Q000473:pathology*; D009830:Olfactory Bulb / Q000166:cytology; D009924:Organ Culture Techniques; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
C491049:Aif1 protein, mouse; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002403:Cathepsins; C028217:cathepsin S
Cathepsin S; Cx3cl1-Cx3cr1 interaction; Niemann-Pick disease type C; microglia; olfaction