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ApoE attenuates unresolvable inflammation by complex formation with activated C1q.

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 (KD~140-580 pM) in vitro, and C1q-ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, A? plaques, and atherosclerosis in vivo. C1q-ApoE complexes in human ChPs, A? 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, A?-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.

SUBMITTER: Yin C

PROVIDER: S-EPMC6420126 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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ApoE attenuates unresolvable inflammation by complex formation with activated C1q.

Yin Changjun C Ackermann Susanne S Ma Zhe Z Mohanta Sarajo K SK Zhang Chuankai C Li Yuanfang Y Nietzsche Sandor S Westermann Martin M Peng Li L Hu Desheng D Bontha Sai Vineela SV Srikakulapu Prasad P Beer Michael M Megens Remco T A RTA Steffens Sabine S Hildner Markus M Halder Luke D LD Eckstein Hans-Henning HH Pelisek Jaroslav J Herms Jochen J Roeber Sigrun S Arzberger Thomas T Borodovsky Anna A Habenicht Livia L Binder Christoph J CJ Weber Christian C Zipfel Peter F PF Skerka Christine C Habenicht Andreas J R AJR

Nature medicine 20190128 3

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<sub>D</sub>~140-580 pM) in vi ...[more]

PMID: 30692699

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Project description:BACKGROUND:Sodium glucose co-transporter2 inhibitors reduce the incidence of cardiovascular events in patients with type 2 diabetes mellitus based on the results of recent cardiovascular outcome studies. Herein, we investigated the effects of long-term treatment with canagliflozin on biochemical and immunohistochemical markers related to atherosclerosis and atherosclerosis development in the aorta of apolipoprotein E knockout (Apo-E(-/-)) mice. METHODS:At the age of 5 weeks, mice were switched from normal to a high-fat diet. After 5 weeks, Apo-E(-/-) mice were divided into control-group (6 mice) treated with 0.5% hydroxypropyl methylcellulose and Cana-group (7 mice) treated with canagliflozin (10 mg/kg per day) per os. After 5 weeks of intervention, animals were sacrificed, and heart and aorta were removed. Sections stained with hematoxylin-eosin (H&E) were used for histomorphometry whereas Masson's stained tissues were used to quantify the collagen content. Immunohistochemistry to assess MCP-1, CD68, a-smooth muscle actin, MMP-2, MMP-9, TIMP-1 and TIMP-2 expression was carried out and q-PCR experiments were performed to quantify mRNA expression. RESULTS:Canagliflozin-group mice had lower total-cholesterol, triglycerides and glucose levels (P?<?0.01), while heart rate was significantly lower (P?<?0.05). Histomorphometry revealed that one in seven Cana-group mice versus four in six control mice developed atheromatosis, while aortic root plaque was significantly less, and collagen was 1.6 times more intense in canagliflozin-group suggesting increased plaque stability. Immunohistochemistry revealed that MCP-1 was significantly less expressed (P?<?0.05) in the aortic root of canagliflozin-group while reduced expression of a-actin and CD68 was not reaching significance (P?=?0.15). VCAM-1 and MCP-1 mRNA levels were lower (P?=?0.02 and P?=?0.07, respectively), while TIMP-1/MMP-2 ratio expression was higher in canagliflozin-group approaching statistical significance (P?=?0.07). CONCLUSIONS:Canagliflozin attenuates the progression of atherosclerosis, reducing (1) hyperlipidemia and hyperglycemia, and (2) inflammatory process, by lowering the expression of inflammatory molecules such as MCP-1 and VCAM-1. Moreover, canagliflozin was found to increase the atherosclerotic plaque stability via increasing TIMP-1/MMP-2 ratio expression.

Dataset Information

ApoE attenuates unresolvable inflammation by complex formation with activated C1q.

Publications

ApoE attenuates unresolvable inflammation by complex formation with activated C1q.

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