The choroid plexus is a key cerebral invasion route for T cells after stroke
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Neuroinflammation contributes substantially to stroke pathophysiology. Cerebral invasion of peripheral leukocytes—particularly T cells—has been shown to be a key event promoting inflammatory tissue damage after stroke. While previous research has focused on the vascular invasion of T cells into the ischemic brain, the choroid plexus (ChP) as an alternative cerebral T-cell invasion route after stroke has not been investigated. We here report specific accumulation of T cells in the peri-infarct cortex and detection of T cells as the predominant population in the ipsilateral ChP in mice as well as in human post-stroke autopsy samples. T-cell migration from the ChP to the peri-infarct cortex was confirmed by in vivo cell tracking of photoactivated T cells. In turn, significantly less T cells invaded the ischemic brain after photothrombotic lesion of the ipsilateral ChP and in a stroke model encompassing ChP ischemia. We detected a gradient of CCR2 ligands as the potential driving force and characterized the neuroanatomical pathway for the intracerebral migration. In summary, our study demonstrates that the ChP is a key invasion route for post-stroke cerebral T-cell invasion and describes a CCR2-ligand gradient between cortex and ChP as the potential driving mechanism for this invasion route.
This work was funded by the excellence cluster of the German research foundation “Munich Cluster for Systems Neurology (SyNergy)” and the German Research foundation (DFG, LI-2534/1-1 and LI-2534/2-1) to A.L. The Swiss National Science Foundation (ProDoc Cell Migration - RM 1 and 3) to BE, the Swiss Heart Foundation to BE and GE. CCR2RFP/RFPCX3CR1GFP/+ were kindly donated by Israel F. Charo (University of California, San Francisco, USA) and Richard Ransohoff (Biogen Idec, Boston, USA). We thank the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center (Los Angeles, USA) for providing human brain samples. The authors would like to thank Kerstin Thuß-Silczakfor excellent technical assistance, Dr. Urban Deutsch for maintaining transgenic mouse colonies at the University of Bern, and Dr. Farida Hellal for advice on histological techniques.
G.L., C.B., X.M., G.E., R.C., T.A., I.L., S.L., and L.M. performed experiments; G.L., C.B., A.G., T.A., R.M., A.E., N.P., B.E. and A.L. analyzed data; J.M. provided critical material and analyzed data; D.V., C.H., N.P., B.E. and G.L. contributed critical input to the manuscript; A.L. initiated the study, designed experiments and wrote the manuscript.
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