Chronic cerebral hypoperfusion activates AIM2 and NLRP3 inflammasome

• Published in: Brain research Vol. 1736; p. 146779
• Main Authors: Matsuyama, Hirofumi, Shindo, Akihiro, Shimada, Takuya, Yata, Kenichiro, Wakita, Hideaki, Takahashi, Ryosuke, Tomimoto, Hidekazu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2020
• Subjects: Chronic cerebral ischemia; Inflammasome; Inflammatory cytokine; Vascular cognitive impairment; White matter lesion; PBS; NOD; IL; AD; BBB; Inflammasome; BCAS; CCAs; DAMPs; White matter lesion; ASC; AIM2; Inflammatory cytokine; Vascular cognitive impairment; NLRP3; Chronic cerebral ischemia; VCI
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2020.146779

•Cerebral hypoperfusion may induce upregulation of NLRP3, AIM2-inflammasomes.•NLRP3 could have a role in the sterile inflammatory responses in astrocytes, and AIM2 in microglia cells.•IL-1β and IL-18 were upregulated in BCAS mice, together with increased expression of the inflammasome.•NLRP3, AIM2-inflammasomes may correlate with neuroinflammation in chronic cerebral ischemia. Inflammation plays an important role in acute and chronic cerebral ischemia. Recent reports indicate that the inflammatory response triggered by tissue damage is mediated by a multiple-protein complex called the inflammasome. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasome complex triggers caspase 1-mediated maturation of interleukin (IL)-1β and IL-18. This study tested the hypothesis that chronic cerebral hypoperfusion activates inflammasomes in the white matter of the brain. To induce cerebral hypoperfusion, C57BL/6J mice were subjected to a sham or bilateral common carotid artery stenosis (BCAS) operation using microcoils with an internal diameter of 0.18 mm. At 2 and 4 weeks after BCAS, the mice were sacrificed (n = 5 in each group). Coronal sections were stained with anti-NLRP3 and anti-AIM2 antibodies. Activation of the inflammasome and cytokines was assessed using immunohistochemistry and cell counting. IL-18 and IL-1β levels were determined by ELISA. Cell counting revealed an increase in NLRP3 and AIM2 inflammasomes at 2 and 4 weeks after BCAS. Immunoreactivity was observed in glial cells in the white matter and corpus callosum. IL-18 and IL-1β concentrations were significantly increased compared with those in the sham operation group. Expression of NLRP3 and AIM2 was upregulated in glial cells in the autopsied brains of patients with cerebral infarction in the chronic phase. These results suggest that chronic cerebral hypoperfusion induces upregulation of NLRP3 and AIM2 inflammasomes; therefore, inflammasomes may play an important role in the sterile inflammatory response in astrocytes and microglia during chronic cerebral hypoperfusion.