Poldip2 controls leukocyte infiltration into the ischemic brain by regulating focal adhesion kinase-mediated VCAM-1 induction

• Type of Material: Article
• Authors: Lori N Eidson, Emory University; Qingzeng Gao, Emory University; Hongyan Qu, Emory University; Daniel S Kikuchi, Emory University; Compos P Ana Carolina, Emory University; Elizabeth A Faidley, Emory University; Yu-Yo Sun, Emory University; Chia-Yi Kuan, Emory University; Rosana L Pagano, Hospital Sírio-Libanês, São Paulo; Bernard Lassegue, Emory University; MariadeLourdes Tansey, Emory University; Kathy Griendling, Emory University; Marina Sorrentino Hernandes, Emory University
• Language: English
• Date: 2021-03-10
• Publisher: NATURE RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-021-84987-z
• Title of Journal or Parent Work: SCIENTIFIC REPORTS
• Volume: 11
• Issue: 1
• Start Page: 5533
• End Page: 5533
• Grant/Funding Information: M.S. Hernandes was supported by AHA 17SDG33410777. K. K. Griendling, M.S. Hernandes and B. Lassègue were supported by NIH HL095070 and NIH HL152167. M.G.T is supported by NIH 1RF1AG057247 and 1RF1AG051514. A.C.P. Campos is supported by FAPESP 2017-14020-4.
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics
• Research Categories: Biology, Neuroscience; Biology, Physiology

Abstract

Stroke is a multiphasic process involving a direct ischemic brain injury which is then exacerbated by the influx of immune cells into the brain tissue. Activation of brain endothelial cells leads to the expression of adhesion molecules such vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells, further increasing leukocyte recruitment. Polymerase δ-interacting protein 2 (Poldip2) promotes brain vascular inflammation and leukocyte recruitment via unknown mechanisms. This study aimed to define the role of Poldip2 in mediating vascular inflammation and leukocyte recruitment following cerebral ischemia. Cerebral ischemia was induced in Poldip2+/+ and Poldip2+/− mice and brains were isolated and processed for flow cytometry or RT-PCR. Cultured rat brain microvascular endothelial cells were used to investigate the effect of Poldip2 depletion on focal adhesion kinase (FAK)-mediated VCAM-1 induction. Poldip2 depletion in vivo attenuated the infiltration of myeloid cells, inflammatory monocytes/macrophages and decreased the induction of adhesion molecules. Focusing on VCAM-1, we demonstrated mechanistically that FAK activation was a critical intermediary in Poldip2-mediated VCAM-1 induction. In conclusion, Poldip2 is an important mediator of endothelial dysfunction and leukocyte recruitment. Thus, Poldip2 could be a therapeutic target to improve morbidity following ischemic stroke.