Research Article: TOPK Promotes Microglia/Macrophage Polarization towards M2 Phenotype via Inhibition of HDAC1 and HDAC2 Activity after Transient Cerebral Ischemia

Date Published: April 1, 2018

Publisher: JKL International LLC

Author(s): Ziping Han, Haiping Zhao, Zhen Tao, Rongliang Wang, Zhibin Fan, Yumin Luo, Yinghao Luo, Xunming Ji.


T-LAK-cell-originated protein kinase (TOPK) is a newly identified member of the mitogen-activated protein kinase family. Our previous study has showed that TOPK has neuroprotective effects against cerebral ischemia-reperfusion injury. Here, we investigated the involvement of TOPK in microglia/ macrophage M1/M2 polarization and the underlying epigenetic mechanism. The expression profiles, co-localization and in vivo interaction of TOPK, M1/M2 surface markers, and HDAC1/HDAC2 were detected after middle cerebral artery occlusion models (MCAO). We demonstrated that TOPK, the M2 surface markers CD206 and Arg1, p-HDAC1, and p-HDAC2 showed a similar pattern of in vivo expression over time after MCAO. TOPK co-localized with CD206, p-HDAC1, and p-HDAC2 positive cells, and was shown to bind to HDAC1 and HDAC2. In vitro study showed that TOPK overexpression in BV2 cells up-regulated CD206 and Arg1, and promoted the phosphorylation of HDAC1 and HDAC2. In addition, TOPK overexpression also prevented LPS plus IFN-γ-induced M1 transformation through reducing release of inflammatory factor of M1 phenotype TNF-α, IL-6 and IL-1β, and increasing TGF-β release and the mRNA levels of TGF-β and SOCS3, cytokine of M2 phenotype and its regulator. Moreover, the increased TNF-α induced by TOPK siRNA could be reversed by HDAC1/HDAC2 inhibitor, FK228. TOPK overexpression increased M2 marker expression in vivo concomitant with the amelioration of cerebral injury, neurological functions deficits, whereas TOPK silencing had the opposite effects, which were completely reversed by the FK228 and partially by the SAHA. These findings suggest that TOPK positively regulates microglia/macrophage M2 polarization by inhibiting HDAC1/HDAC2 activity, which may contribute to its neuroprotective effects against cerebral ischemia-reperfusion injury.

Partial Text

Cumulative studies indicate that the dual role of activated microglia/macrophages depends on the transition between the “classically activated” pro-inflammatory M1 phenotype and the “alternatively activated” neuroprotective M2 phenotype [20-25]. This suggests that regulating the phenotype transition may be a promising target for ischemic stroke therapy. Several studies report the involvement of TOPK in inflammatory responses [26, 27]. However, the function of TOPK in microglia/macrophage M1/M2 polarization following brain ischemic injury remains unknown. In the current study, we showed that TOPK expression after cerebral ischemia-reperfusion followed a similar pattern to that of the M2 surface markers CD206 and Arg1. Furthermore, TOPK co-localized with CD206 in the ischemic region. Our in vitro studies demonstrated that TOPK overexpression significantly up-regulated CD206 and Arg1 in BV2 cells. These data highlighted the critical importance of TOPK in driving microglia/macrophage polarization towards the M2 phenotype following cerebral ischemia-reperfusion injury, and suggested that TOPK might be a potential therapeutic target in ischemic stroke. However, TOPK overexpression also had values both as a predictive biomarker and prognostic factor in lung cancer, ovarian cancer and skin inflammation, which made TOPK silencing or inhibition a potential therapeutic target in these diseases [28-30]. Above all, we have to think over carefully before we translate those scientific achievements into clinical application, and the TOPK activity should been brought under cautious control in a dose and time dependent manner.




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