The choroid plexus is a key cerebral invasion route for T cells after stroke

Abstract

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.

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

“…It was proposed that CP plays a major role as the invasion route for T-cells into the ischemic brain following a stroke. The mechanism of migration is probably based on a potential chemokine gradient between the CP and the cortical ischemic lesion [219]. A similar mechanism was found in monocyte-derived macrophages that were increased in the CP and CSF during the first week after ischemic insult.…”

“…↓ CSF secretion [198] ↑ mRNA for NF-κB, MCP-1, IL1R1, IL-8, IL-6, FAS, TNF-α expression [183] ↑ Iba-1+ and CD68+ epiplexus cells [186] ↑ Number of cytoplasmic water vesicles [191][192][193] ↑ HO-1 expression [183] ↑ AQP1 expression [194] Activation of TLR4 [182] Ischemic Apoptosis or necrosis according to the severity of ischemic injury [201] ↑ ED1+ number, CR3 receptors, expression of MHC I and MHC II antigens [217] ↑ Calcium transfer to CSF [210] Alteration in B-CSF barrier after middle cerebral artery occlusion [207] ↑ Apoptotic cells characterized by nuclear DNA fragmentation after middle cerebral artery occlusion [201] ↑ iNOS expression in epiplexus cells, Number of OX-42+ , ED1+ , OX-18+ , OX-6+ cells in epiplexus position [217] ↑ Permeability of B-CSF barrier for inulin after bilateral carotid occlusion [205] ↑ Expression of TGFβ1, brain-derived neurotrophic factor and other growth factors [216] ↑ MMP-9 expression in infiltrating macrophages [214] ↑ VEGF and eNOS expression [217,218] Plasma membrane and organelle damage; clumping of nuclear chromatin after forebrain ischemia [205,206] ↑ Number of macrophages [220] ↑ CP epithelial cell proliferation Expression of NeuN and GFAP after middle cerebral artery occlusion [215] CP as invasion route for T cells into the ischemic brain [219] Edema, apoptosis of CP epithelial cells after middle cerebral artery occlusion Indistinct epithelial membranes and varying degrees of pyknosis after middle cerebral artery occlusion [214] Desquamation of CP epithelial cells [199] ↓ AQP1 expression up to 24 h ↑ AQP1expression between 24-48 h after global cerebral ischemia [209] ↑ VCAM-1, MAdCAM-1, C3CL1, Nt5e expression [220] Traumatic TBI ↑ Intercellular spaces between CP epithelial cells [225] ↑ Macrophage number in epiplexus position after non-penetrative injury…”

Panoptic vDISCO imaging reveals neuronal connectivity, remote trauma effects and meningeal vessels in intact transparent mice

“…LysM GFP+ cells also increased in the meningeal structures of MCAO mice ( Fig. 4k cyan arrowheads) suggesting that the meninges might be playing a role as entry and/or exit route of the brain in addition to the disrupted blood brain-barrier and the choroid plexus 36 . Finally, we explored the inflammatory reaction after spinal cord injury (SCI) using panoptic imaging.…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Investigating T-cell invasion into the peri-infarct cortex after ischemic stroke by employing in vivo cell tracking of photactivated T cells has indeed provided evidence for a directed intracerebral migration of T cells from the ipsilateral choroid plexus stroma to the peri-infarct cortex [83]. A CCR2 ligand gradient between the choroid plexus stroma and the ischemic cortex was identified as the potential driving mechanism for T cell invasion.…”

“…A CCR2 ligand gradient between the choroid plexus stroma and the ischemic cortex was identified as the potential driving mechanism for T cell invasion. At the same time blocking CSF flow with matrigel failed to alter T cell invasion at the peri-ischemic site suggesting that T cell migration via ventricular CSF does not play a significant role in cerebral T cell invasion after stroke [83]. A route of immune cell entry from the choroid plexus stroma into the CNS other than passing through the epithelium, e.g.…”