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

Abstract

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.

Immune changes in peripheral blood and hematoma of patients with intracerebral hemorrhage

“…Additional studies with a larger sample size are needed to validate our findings. Moreover, we identified M1‐ and M2‐like M/MΦ only by using surface markers, such as CD45, CD11b, CD86, and CD206, as indicated in animals . Monocytes, macrophages, and microglia have large overlap in surface markers including CD11b, CD86, and CD206.…”

“…Moreover, we identified M1-and M2like M/MΦ only by using surface markers, such as CD45, CD11b, CD86, and CD206, as indicated in animals. 52,75,88 Monocytes, macrophages, and microglia have large overlap in surface markers including CD11b, CD86, and CD206. There is currently no consensus on how to identify resident microglia and infiltrating myeloid cells using specific surface markers under inflammatory conditions.…”

Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury

“…CIP promotes TOPK phosphorylation, significantly enhances TOPK activity, and reduces reperfusion injury (Zhao et al, 2014a). Further findings suggest that TOPK positively regulates microglia/macrophage M2 polarization by inhibiting histone deacetylase (HDAC) 1/HDAC2 activity, which regulated inflammatory responses by participating in the microglia/macrophages M1/M2 polarization (Wang et al, 2015;Zhao et al, 2016;Han et al, 2018), and may contribute to its neuroprotective effects against CIRI (Han et al, 2018). Previous mechanism studies have shown that ERK is the downstream signal of TOPK, and that the PI3K/PTEN/Akt and PBK signaling pathways are also involved in the TOPK regulation process (Gao et al, 2016;Sun et al, 2016).…”

Intravenous antagomiR‐494 lessens brain‐infiltrating neutrophils by increasing HDAC2‐mediated repression of multiple MMPs in experimental stroke

“…HDAC2 belongs to the class I HDACs and is known to act as epigenetic and transcriptional regulators. It was already known that HDAC2 could regulate the phenotype shift of T helper cells, microglia, and macrophages 13‐15 . However, whether miR‐494 and its target HDAC2 are implicated in brain infiltration of neutrophil or phenotypic transformation following ischemic stroke is not clear.…”