Complement controls choroid plexus inflammation

Identification: Yin, Changjun


Complement controls choroid plexus inflammation
Changjun Yin1, Zhe Ma1, Sarajo K. Mohanta1, Yuanfang Li1, Sai Vineela Bontha2, Michael Beer3, Anna Borodovsky4, Christian Weber1,  and Andreas J.R. Habenicht1
1Institute for Cardiovascular Prevention, LMU, Munich; 2Department of Surgery, University of Virginia, U.S.A.; 3Department of Information Technology, University Clinic Jena; 4Alnylam Pharmaceuticals, USA
The choroid plexus (ChP) is the major intracranial neuroimmunological interface which produces the cerebrospinal fluid (CSF), forms the blood-CSF barrier, exchanges signals between the brain and the circulation, and is the principal gateway for blood-borne leukocytes to infiltrate the central nervous system in inflammatory and degenerative brain diseases. However, the impact of vascular risk factors, i.e. hyperlipidemia, age, and ApoE isoforms on ChPs largely remain to be determined. By using aged WT, ApoE-/-, normal-chow (NC) or high fat diet-fed (HFD) ApoE3-knockin (ApoE3-KI), or  NC and HFD-fed ApoE4-KI mice, we observed similar amounts of lipid in aged ApoE-/- and HFD ApoE4-KI ChPs but no lipid accumulated in NC ApoE4-KI or in NC or HFD ApoE3-KI ChPs. Extracellular lipid deposits colocalized with leukocytes in ApoE-/- ChPs with the majority of macrophages/dendritic cells (DCs). Moreover, ChP leukocytes, endothelial cells, and epithelial cells accumulated intracellular lipid droplets. Expression microarrays of ChPs identified a marked number of transcripts of immune response-regulating genes. In addition, a major ApoE4-isoform-specific interferon-related gene cluster was identified. Lipid associated with complement C1q, C4, C3, and C5 components. To examine whether lipid-triggered complement activation participates in leukocyte infiltration in ChPs, we chose to specifically target liver-derived C5 using a small interference RNA (siRNA) that selectively binds to the liver asialoglycoprotein receptor. Liver C5-siRNA knockdown led to a large decrease of circulating C5 levels, attenuated CD45+ leukocyte-, CD68+ macrophage-/DC-, and CD3+ T-cell infiltration in ApoE-/- ChP. These data revealed independent though synergistic impacts of ApoE4 and hyperlipidemia on ChP inflammation and support the conclusion that lipid-triggered complement activation controls ChP leukocyte infiltration.


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