CNS-associated macrophages contribute to intracerebral aneurysm pathophysiology

Acta Neuropathologica Communications - Tập 12 Số 1
Martina Glavan1, Andrea Jelić1, Damien Levard1, Juhana Frösén2, Sara Keränen2, Bart A. A. Franx3, Ana Rita Brás4, Estelle R Louet1, Ádám Dénes4, Mario Merlini1, Denis Vivien5, Marina Rubio1
1UNICAEN, INSERM U1237, Etablissement Français du Sang, Physiopathology and Imaging of Neurological Disorders (PhIND), Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C), PHIND Boulevard Henri Becquerel, Normandie University, 14000, Caen Cedex, Caen, France
2Hemorrhagic Brain Pathology Research Group, Kuopio University Hospital and AIV Institute for Molecular Medicine, University of Eastern Finland, Kuopio, Finland
3Translational Neuroimaging Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
4"Momentum" Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary
5Department of Clinical Research, Caen Normandie University Hospital, Caen, France

Tóm tắt

AbstractIntracerebral aneurysms (IAs) are pathological dilatations of cerebral arteries whose rupture leads to subarachnoid hemorrhage, a significant cause of disability and death. Inflammation is recognized as a critical contributor to the formation, growth, and rupture of IAs; however, its precise actors have not yet been fully elucidated. Here, we report CNS-associated macrophages (CAMs), also known as border-associated macrophages, as one of the key players in IA pathogenesis, acting as critical mediators of inflammatory processes related to IA ruptures. Using a new mouse model of middle cerebral artery (MCA) aneurysms we show that CAMs accumulate in the IA walls. This finding was confirmed in a human MCA aneurysm obtained after surgical clipping, together with other pathological characteristics found in the experimental model including morphological changes and inflammatory cell infiltration. In addition, in vivo longitudinal molecular MRI studies revealed vascular inflammation strongly associated with the aneurysm area, i.e., high expression of VCAM-1 and P-selectin adhesion molecules, which precedes and predicts the bleeding extent in the case of IA rupture. Specific CAM depletion by intracerebroventricular injection of clodronate liposomes prior to IA induction reduced IA formation and rupture rate. Moreover, the absence of CAMs ameliorated the outcome severity of IA ruptures resulting in smaller hemorrhages, accompanied by reduced neutrophil infiltration. Our data shed light on the unexplored role of CAMs as main actors orchestrating the progression of IAs towards a rupture-prone state. Graphical abstract

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Tập 12 Số 1

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