ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Changjun Yin; Susanne Ackermann; Zhe Ma; Sarajo K. Mohanta; Chuankai Zhang; Yuanfang Li; Sandor Nietzsche; Martin Westermann; Li Peng; Desheng Hu; Sai Vineela Bontha; Prasad Srikakulapu; Michael Beer; Remco T. A. Megens; Sabine Steffens; Markus Hildner; Luke D. Halder; Hans-Henning Eckstein; Jaroslav Pelisek; Jochen Herms; Sigrun Roeber; Thomas Arzberger; Anna Borodovsky; Livia Habenicht; Christoph J. Binder; Christian Weber; Peter F. Zipfel; Christine Skerka; Andreas J. R. Habenicht

doi:10.1038/s41591-018-0336-8

ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Changjun Yin^*, Susanne Ackermann, Zhe Ma, Sarajo K. Mohanta, Chuankai Zhang, Yuanfang Li, Sandor Nietzsche, Martin Westermann, Li Peng, Desheng Hu, Sai Vineela Bontha, Prasad Srikakulapu, Michael Beer, Remco T. A. Megens, Sabine Steffens, Markus Hildner, Luke D. Halder, Hans-Henning Eckstein, Jaroslav Pelisek, Jochen HermsSigrun Roeber, Thomas Arzberger, Anna Borodovsky, Livia Habenicht, Christoph J. Binder, Christian Weber, Peter F. Zipfel, Christine Skerka^*, Andreas J. R. Habenicht

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 (K _D~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.

Original language	English
Pages (from-to)	496-506
Number of pages	23
Journal	Nature Medicine
Volume	25
Issue number	3
DOIs	https://doi.org/10.1038/s41591-018-0336-8
Publication status	Published - 1 Mar 2019

Keywords

A-BETA
ALZHEIMERS-DISEASE
APOLIPOPROTEIN-E
ATHEROSCLEROSIS
FACTOR-H BINDS
IMMUNE
LASER-CAPTURE MICRODISSECTION
MICE
NEURODEGENERATION
NEUROFIBRILLARY PATHOLOGY
Laser-capture microdissection
Apolipoprotein-e
Immune
A-beta
Neurodegeneration
Atherosclerosis
Neurofibrillary pathology
Mice
Alzheimers-disease
Factor-h binds

Access to Document

10.1038/s41591-018-0336-8Licence: Unspecified

1 Erratum / corrigendum / retractions

Publisher Correction: ApoE attenuates unresolvable inflammation by complex formation with activated C1q
Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., Bontha, S. V., Srikakulapu, P., Beer, M., Megens, R. T. A., Steffens, S., Hildner, M., Halder, L. D., Eckstein, H-H., Pelisek, J., Herms, J., & 9 othersRoeber, S., Arzberger, T., Borodovsky, A., Habenicht, L., Binder, C. J., Weber, C., Zipfel, P. F., Skerka, C. & Habenicht, A. J. R., Mar 2019, In: Nature Medicine. 25, 3, p. 529-529 1 p.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

Cite this

Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., Bontha, S. V., Srikakulapu, P., Beer, M., Megens, R. T. A., Steffens, S., Hildner, M., Halder, L. D., Eckstein, H.-H., Pelisek, J., ... Habenicht, A. J. R. (2019). ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nature Medicine, 25(3), 496-506. https://doi.org/10.1038/s41591-018-0336-8

@article{483351696d0e4189b9b94afe4aae32c9,

title = "ApoE attenuates unresolvable inflammation by complex formation with activated C1q",

abstract = "Apolipoprotein-E (ApoE) has been implicated in Alzheimer{\textquoteright}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 (K D~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.",

keywords = "A-BETA, ALZHEIMERS-DISEASE, APOLIPOPROTEIN-E, ATHEROSCLEROSIS, FACTOR-H BINDS, IMMUNE, LASER-CAPTURE MICRODISSECTION, MICE, NEURODEGENERATION, NEUROFIBRILLARY PATHOLOGY, Laser-capture microdissection, Apolipoprotein-e, Immune, A-beta, Neurodegeneration, Atherosclerosis, Neurofibrillary pathology, Mice, Alzheimers-disease, Factor-h binds",

author = "Changjun Yin and Susanne Ackermann and Zhe Ma and Mohanta, {Sarajo K.} and Chuankai Zhang and Yuanfang Li and Sandor Nietzsche and Martin Westermann and Li Peng and Desheng Hu and Bontha, {Sai Vineela} and Prasad Srikakulapu and Michael Beer and Megens, {Remco T. A.} and Sabine Steffens and Markus Hildner and Halder, {Luke D.} and Hans-Henning Eckstein and Jaroslav Pelisek and Jochen Herms and Sigrun Roeber and Thomas Arzberger and Anna Borodovsky and Livia Habenicht and Binder, {Christoph J.} and Christian Weber and Zipfel, {Peter F.} and Christine Skerka and Habenicht, {Andreas J. R.}",

note = "Funding Information: We thank W. Schneider, Medical University of Vienna, Austria, for advice; T. Hallstr{\"o}m, Y. Lin, and S. H{\"a}lbich, Leibniz Institute for Natural Product Research and Infection Biology, Jena, for performing complement assays; W. Wilfert, Institute of Laboratory Medicine, University of Munich for lipid analyses; S. Schmidt, Institute for Experimental Neurology, Jena, for advice; and N. Buresch, Center for Neuropathology and Prion Research, Munich, for technical assistance; M. Jucker, Hertie Institute for Clinical Brain Research, University of T{\"u}bingen, for experimental support. This work was funded by the Deutsche Forschungsgemeinschaft (DFG): YI 133/2-1 to C.Y.; HA 1083/15-4 to A.J.R.H.; MO 3054/1-1 to S.M.; The German Collaborative Research Center (CRC124/2-C4), SK46/2 to C.S.; CRC124/2-C6 and DFG TR 1992 to P.F.Z.; the German Centre for Cardiovascular Research (DZHK MHA VD1.2), DFG SFB 1123/A1 and Z3, the European Research Council (ERC AdG 692511) to C.W.; SFB1123/Z01, INST409/150-1 FUGG to R.T.A.M.; Chinese National Natural Science Foundation (31770983) to D.H.; S.A. and L.D.H. are doctoral researchers at the International Leibniz Research School (ILRS) in Jena. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = mar,

day = "1",

doi = "10.1038/s41591-018-0336-8",

language = "English",

volume = "25",

pages = "496--506",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "3",

}

Yin, C, Ackermann, S, Ma, Z, Mohanta, SK, Zhang, C, Li, Y, Nietzsche, S, Westermann, M, Peng, L, Hu, D, Bontha, SV, Srikakulapu, P, Beer, M, Megens, RTA, Steffens, S, Hildner, M, Halder, LD, Eckstein, H-H, Pelisek, J, Herms, J, Roeber, S, Arzberger, T, Borodovsky, A, Habenicht, L, Binder, CJ, Weber, C, Zipfel, PF, Skerka, C & Habenicht, AJR 2019, 'ApoE attenuates unresolvable inflammation by complex formation with activated C1q', Nature Medicine, vol. 25, no. 3, pp. 496-506. https://doi.org/10.1038/s41591-018-0336-8

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 - Funding Information: We thank W. Schneider, Medical University of Vienna, Austria, for advice; T. Hallström, Y. Lin, and S. Hälbich, Leibniz Institute for Natural Product Research and Infection Biology, Jena, for performing complement assays; W. Wilfert, Institute of Laboratory Medicine, University of Munich for lipid analyses; S. Schmidt, Institute for Experimental Neurology, Jena, for advice; and N. Buresch, Center for Neuropathology and Prion Research, Munich, for technical assistance; M. Jucker, Hertie Institute for Clinical Brain Research, University of Tübingen, for experimental support. This work was funded by the Deutsche Forschungsgemeinschaft (DFG): YI 133/2-1 to C.Y.; HA 1083/15-4 to A.J.R.H.; MO 3054/1-1 to S.M.; The German Collaborative Research Center (CRC124/2-C4), SK46/2 to C.S.; CRC124/2-C6 and DFG TR 1992 to P.F.Z.; the German Centre for Cardiovascular Research (DZHK MHA VD1.2), DFG SFB 1123/A1 and Z3, the European Research Council (ERC AdG 692511) to C.W.; SFB1123/Z01, INST409/150-1 FUGG to R.T.A.M.; Chinese National Natural Science Foundation (31770983) to D.H.; S.A. and L.D.H. are doctoral researchers at the International Leibniz Research School (ILRS) in Jena. 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 (K D~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 (K D~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.

KW - A-BETA

KW - ALZHEIMERS-DISEASE

KW - APOLIPOPROTEIN-E

KW - ATHEROSCLEROSIS

KW - FACTOR-H BINDS

KW - IMMUNE

KW - LASER-CAPTURE MICRODISSECTION

KW - MICE

KW - NEURODEGENERATION

KW - NEUROFIBRILLARY PATHOLOGY

KW - Laser-capture microdissection

KW - Apolipoprotein-e

KW - Immune

KW - A-beta

KW - Neurodegeneration

KW - Atherosclerosis

KW - Neurofibrillary pathology

KW - Mice

KW - Alzheimers-disease

KW - Factor-h binds

U2 - 10.1038/s41591-018-0336-8

DO - 10.1038/s41591-018-0336-8

M3 - Article

C2 - 30692699

SN - 1078-8956

VL - 25

SP - 496

EP - 506

JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -

ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Abstract

Keywords

Access to Document

Research output

Publisher Correction: ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Cite this