TY - JOUR
T1 - ApoE attenuates unresolvable inflammation by complex formation with activated C1q
AU - Yin, Changjun
AU - Ackermann, Susanne
AU - Ma, Zhe
AU - Mohanta, Sarajo K.
AU - Zhang, Chuankai
AU - Li, Yuanfang
AU - Nietzsche, Sandor
AU - Westermann, Martin
AU - Peng, Li
AU - Hu, Desheng
AU - Bontha, Sai Vineela
AU - Srikakulapu, Prasad
AU - Beer, Michael
AU - Megens, Remco T.A.
AU - Steffens, Sabine
AU - Hildner, Markus
AU - Halder, Luke D.
AU - Eckstein, Hans Henning
AU - Pelisek, Jaroslav
AU - Herms, Jochen
AU - Roeber, Sigrun
AU - Arzberger, Thomas
AU - Borodovsky, Anna
AU - Habenicht, Livia
AU - Binder, Christoph J.
AU - Weber, Christian
AU - Zipfel, Peter F.
AU - Skerka, Christine
AU - Habenicht, Andreas J.R.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Apolipoprotein-E (ApoE) has been implicated in Alzheimer’s disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP). All human ApoE isoforms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (KD~140–580 pM) in vitro, and C1q–ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, Aβ plaques, and atherosclerosis in vivo. C1q–ApoE complexes in human ChPs, Aβ plaques, and arteries correlated with cognitive decline and atherosclerosis, respectively. Treatment with small interfering RNA (siRNA) against C5, which is formed by all complement pathways, attenuated murine ChP inflammation, Aβ-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.
AB - Apolipoprotein-E (ApoE) has been implicated in Alzheimer’s disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP). All human ApoE isoforms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (KD~140–580 pM) in vitro, and C1q–ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, Aβ plaques, and atherosclerosis in vivo. C1q–ApoE complexes in human ChPs, Aβ plaques, and arteries correlated with cognitive decline and atherosclerosis, respectively. Treatment with small interfering RNA (siRNA) against C5, which is formed by all complement pathways, attenuated murine ChP inflammation, Aβ-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.
UR - http://www.scopus.com/inward/record.url?scp=85060805711&partnerID=8YFLogxK
U2 - 10.1038/s41591-018-0336-8
DO - 10.1038/s41591-018-0336-8
M3 - Article
C2 - 30692699
AN - SCOPUS:85060805711
SN - 1078-8956
VL - 25
SP - 496
EP - 506
JO - Nature Medicine
JF - Nature Medicine
IS - 3
ER -
