The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

Abstract

contributed equally to the research work.Abbreviations: AIM2, absent in melanoma 2; ASC, apoptosis speck-like protein; BBB, brain-blood barrier; DAMPs, damaged-associated molecular patterns; ECA, external carotid artery; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein; HDAC3, histone deacetylases 3; Iba-1, ionized calcium binding adaptor molecule 1; LPS, lipopolysaccharide; MCAO, middle cerebral artery occlusion; NeuN, neuronal nuclei; Nrf2, nuclear factor E2-related factor-2; PYD, N-terminal pyrin domain; TTC, 2,3,5-triphenyltetrazolium chloride AbstractHistone deacetylases 3 (HDAC3) modulates the acetylation state of histone and nonhistone proteins and could be a powerful regulator of the inflammatory process in stroke. Inflammasome activation is a ubiquitous but poorly understood consequence of acute ischemic stroke. Here, we investigated the potential contributions of HDAC3 to inflammasome activation in primary cultured microglia and experimental stroke models. In this study, we documented that HDAC3 expression was increased in microglia of mouse experimental stroke model. Intraperitoneal injection of RGFP966 (a selective inhibitor of HDAC3) decreased infarct size and alleviated neurological deficits after the onset of middle cerebral artery occlusion (MCAO). In vitro data indicated that LPS stimulation evoked a time-dependent increase of HDAC3 and absent in melanoma 2 (AIM2) inflammasome in primary cultured microglia.Interestingly, AIM2 was subjected to spatiotemporal regulation by RGFP966. The ability of RGFP966 to inhibit the AIM2 inflammasome was confirmed in an experimental mouse model of stroke. As expected, AIM2 knockout mice also demonstrated significant resistance to ischemia injury compared with their wild-type littermates. RGFP966 failed to exhibit extra protective effects in AIM2−/− stroke mice. Furthermore, we found that RGFP966 enhanced STAT1 acetylation and subsequently attenuated STAT1 phosphorylation, which may at least partially contributed to the negative regulation of AIM2 by RGFP966. Together, we initially found that RGFP966 alleviated the inflammatory response and protected against ischemic stroke by regulating the AIM2 inflammasome. K E Y W O R D SAIM2 inflammasome, HDAC3, microglia, STAT1, stroke | 649 ZHANG et Al.

Updating a Strategy for Histone Deacetylases and Its Inhibitors in the Potential Treatment of Cerebral Ischemic Stroke

“…Furthermore, T-LAK-cell-originated protein kinase (TOPK) has a neuroprotective effect on cerebral ischemia-reperfusion injury by inhibiting HDAC1/HDAC2 activity, which may be related to the neuroprotective effect of TOPK on cerebral ischemia-reperfusion injury [ 30 ]. The expression of HDAC3 in the pathological process of diabetes and stroke can protect the brain from ischemia-reperfusion (I/R) injury by regulating oxidative stress, apoptosis, and autophagy in vivo and in vitro, and the mechanisms may be by the upregulated expressions of brain and muscle ARNT-Like 1 and AIM2 inflammatory bodies [ 31 , 32 ]. Calpeptin pretreatment blocked the attenuation of the nuclear distribution of HDAC3 in vivo [ 33 ].…”

Gonadal Hormones E2 and P Mitigate Cerebral Ischemia-Induced Upregulation of the AIM2 and NLRC4 Inflammasomes in Rats

“…Most recent studies further underlined the role of AIM2 and NLRC4 in the post-ischemic pathophysiology. For instance, treatment with the histone deacetylases 3 (HDAC3) inhibitor reduced infarct sizes, most probably mediated by a downregulation of AIM2 after acute ischemia [ 10 ]. Nevertheless, the role of AIM2 or NLRC4 in the context of acute ischemia has been little researched so far.…”

AIM2 in health and disease: Inflammasome and beyond

“…81 The AIM2 inflammasome also plays detrimental roles in several types of brain injury such as ischemic brain injury, cerebral ischemic reperfusion injury, subarachnoid hemorrhagia, and traumatic brain injury. [82][83][84][85] Additional inflammatory roles of AIM2 have been reported in vascular diseases such as atherosclerosis and cardiomyopathy. 86 Atherosclerosis-prone ApoE -/mice fed a high-fat diet showed enhanced expression of AIM2 in vascular smooth muscle cells (VSMCs), which correlated with high ICAM-1 expression in these cells.…”