Inhibition of TGFβ-activated kinase 1 promotes inflammation-resolving microglial/macrophage responses and recovery after stroke in ovariectomized female mice

Abstract

TGFβ-activated kinase 1 (TAK1) is a master regulator that drives multiple cell death and proinflammatory signaling pathways, making it a promising therapeutic target to treat ischemic stroke. However, whether targeting TAK1 could improve stroke outcomes has never been tested in female subjects, hindering its potential translation into clinical use. Here we examined the therapeutic effect of 5Z-7-Oxozeaenol (OZ), a selective TAK1 inhibitor, in ovariectomized female mice after middle cerebral artery occlusion (MCAO). OZ significantly reduced neuronal cell death and axonal injury at the acute stage and mitigated neuroinflammation at the subacute stage after MCAO in ovariectomized female mice. Consistent with RNA sequencing analysis that TAK1 activation contributed to microglia/macrophage-mediated inflammatory responses in the post-stroke brain, inhibition of TAK1 with OZ caused phenotypic shift of microglia/macrophages toward an inflammation-resolving state. Furthermore, microglia/macrophage-specific TAK1 knockout (TAK1 mKO) reproduced OZ's effects, causally confirming the role of TAK1 in determining proinflammatory microglial/macrophage responses in post-stroke females. Post-stroke treatment with OZ for 5 days effectively promoted long-term neurological recovery and the integrity of both gray matter and white matter in female mice. Together, the TAK1 inhibitor OZ elicits long-lasting improvement of stroke outcomes in female mice, at least partially through enhancing beneficial microglial/macrophage responses and inflammation resolution. Given its therapeutic efficacy on both male and female rodents, TAK1 inhibitor is worth further investigation as a valid treatment to ischemic stroke.

Keywords: 5Z-7-Oxozeaenol; Inflammation; MAP3K7; Ovariectomized mice; TAK1; Transient focal cerebral ischemia.