N‐myc downstream‐regulated gene 2 protects blood–brain barrier integrity following cerebral ischemia

• Published in: Glia 2018-07, Vol.66 (7), p.1432-1446
• Main Authors: Takarada‐Iemata, Mika, Yoshikawa, Akifumi, Ta, Hieu Minh, Okitani, Nahoko, Nishiuchi, Takumi, Aida, Yasuhiro, Kamide, Tomoya, Hattori, Tsuyoshi, Ishii, Hiroshi, Tamatani, Takashi, Le, Thuong Manh, Roboon, Jureepon, Kitao, Yasuko, Matsuyama, Tomohiro, Nakada, Mitsutoshi, Hori, Osamu
• Format: Article
• Language: English
• Subjects: Astrocytes; Blood-brain barrier; Brain; Cell culture; Cerebral blood flow; Clonal deletion; Extravasation; Fibrinogen; Immune system; Infiltration; inflammation; Integrity; Ischemia; matrix metalloproteinase; Matrix metalloproteinases; Membrane permeability; Mice; Molecular chains; Myc protein; Occlusion; Permeability; Proteins; Rodents; Serum proteins
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23315

Disruption of the blood‐brain barrier (BBB) following cerebral ischemia is closely related to the infiltration of peripheral cells into the brain, progression of lesion formation, and clinical exacerbation. However, the mechanism that regulates BBB integrity, especially after permanent ischemia, remains unclear. Here, we present evidence that astrocytic N‐myc downstream‐regulated gene 2 (NDRG2), a differentiation‐ and stress‐associated molecule, may function as a modulator of BBB permeability following ischemic stroke, using a mouse model of permanent cerebral ischemia. Immunohistological analysis showed that the expression of NDRG2 increases dominantly in astrocytes following permanent middle cerebral artery occlusion (MCAO). Genetic deletion of Ndrg2 exhibited enhanced levels of infarct volume and accumulation of immune cells into the ipsilateral brain hemisphere following ischemia. Extravasation of serum proteins including fibrinogen and immunoglobulin, after MCAO, was enhanced at the ischemic core and perivascular region of the peri‐infarct area in the ipsilateral cortex of Ndrg2‐deficient mice. Furthermore, the expression of matrix metalloproteinases (MMPs) after MCAO markedly increased in Ndrg2−/− mice. In culture, expression and secretion of MMP‐3 was increased in Ndrg2−/− astrocytes, and this increase was reversed by adenovirus‐mediated re‐expression of NDRG2. These findings suggest that NDRG2, expressed in astrocytes, may play a critical role in the regulation of BBB permeability and immune cell infiltration through the modulation of MMP expression following cerebral ischemia. Main Points Ndrg2 deficiency causes enhanced BBB permeability following brain ischemia. NDRG2 negatively regulates MMP‐3 expression cell‐autonomously and MMP‐9 expression non‐cell‐autonomously. Astrocytic NDRG2 plays protective roles in brain ischemia.