Cyclophilin a signaling induces pericyte-associated blood-brain barrier disruption after subarachnoid hemorrhage

Pengyu Pan,Jie Qu,Haiyang He,Shilun Zuo,John H Zhang,Xuan Zhang,Qiang Li,Guobiao Liang,Fan Yang,Hengli Zhao,Hua Feng,Yujie Chen,Xin Liu

doi:10.1186/s12974-020-1699-6

Abstract

ObjectiveThe potential roles and mechanisms of pericytes in maintaining blood–brain barrier (BBB) integrity, which would be helpful for the development of therapeutic strategies for subarachnoid hemorrhage (SAH), remain unclear. We sought to provide evidence on the potential role of pericytes in BBB disruption and possible involvement and mechanism of CypA signaling in both cultured pericytes and SAH models.MethodsThree hundred fifty-three adult male C57B6J mice weighing 22 to 30 g, 29 CypA−/− mice, 30 CypA+/+ (flox/flox) mice, and 30 male neonatal C57B6J mice were used to investigate the time course of CypA expression in pericytes after SAH, the intrinsic function and mechanism of CypA in pericytes, and whether the known receptor CD147 mediates these effects.ResultsOur data demonstrated both intracellular CypA and CypA secretion increased after SAH and could activate CD147 receptor and downstream NF-κB pathway to induce MMP9 expression and proteolytic functions for degradation of endothelium tight junction proteins and basal membranes. CypA served as autocrine or paracrine ligand for its receptor, CD147. Although CypA could be endocytosed by pericytes, specific endocytosis inhibitor chlorpromazine did not have any effect on MMP9 activation. However, specific knockdown of CD147 could reverse the harmful effects of CypA expression in pericytes on the BBB integrity after SAH.ConclusionsThis study demonstrated for the first time that CypA mediated the harmful effects of pericytes on BBB disruption after SAH, which potentially mediated by CD147/NF-κB/MMP9 signal, and junction protein degradation in the brain. By targeting CypA and pericytes, this study may provide new insights on the management of SAH patients.

Highlights

Despite years of research, early brain injury, which is the main contributor to the mortality and poor prognosis of patients after subarachnoid hemorrhage (SAH), remains a worrisome complication of ruptured intracranial aneurysms [1]
Cyclophilin A (CypA) expression in pericytes after SAH To investigate the expression of CypA in the pericytes after SAH induction, we detected the protein levels of CypA in the microvessels of the brain specimen from the mice after SAH induction and in the cultured pericytes after Hb stimulation
Immunohistochemical staining at 24 h after SAH showed that CypA expression was colocalized with the pericyte markers, Lectin and PDGFRβ/CD13, in the left/ipsilateral cortex (Fig. 1b)

Summary

Introduction

Early brain injury, which is the main contributor to the mortality and poor prognosis of patients after subarachnoid hemorrhage (SAH), remains a worrisome complication of ruptured intracranial aneurysms [1]. The pathophysiology of SAH and other stroke events involves changes in the cerebral vascular neural network, including the arterial and venous systems as well as neuronal cells, other support cells, and cellular. Pan et al Journal of Neuroinflammation (2020) 17:16 pericytes bidirectionally control microvessel diameters and regulate cerebral blood flow [4]. Our previous study further demonstrated that pericyte α-SMA phenotype transformation caused acute microvessel/pearl-like constriction and neurological deficits in the setting of SAH [5, 6]. A recent study suggested that pericytes might have a negative influence on neurovascular integrity and cause neuronal degeneration in apolipoprotein E-deficient mice [7]. More direct evidence was found using a two-photon microscope, which showed that pericytes contribute to rapid and localized proteolytic degradation around pericyte somata during ischemia [8]

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