DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

Abstract

Background: Intracerebral hemorrhage (ICH) is the most devastating stroke subtype, with a poor prognosis and few proven treatments. Neuroinflammation is associated with ICH-induced brain injury and unfavorable outcomes. There is growing evidence that Dickkopf (DKK) 3 plays a key role in the adaptive anti-inflammatory and neuroprotective responses following intracerebral hemorrhage. This study aimed to evaluate the protective effects of DKK3 against brain edema and neuroinflammation in a mice model of ICH. Methods: Male, adult CD1 mice were subjected to sham or ICH surgery using a collagenase injection model. ICH animals received either recombinant DKK3, Kremen-1 siRNA, or DVL-1 siRNA. The neurobehavioral deficits were evaluated at 24 h, 72 h, and 28 days after ICH induction. Western blot and immunofluorescence were employed to examine the expression and localization of DKK3, Kremen-1, Dishevelled-1 (DVL-1), c-JUN N-terminal kinase (JNK), Activator protein-1 (AP-1), cleaved caspase-1, NF-κB, and IL-1β in the brain. Results: The expression of endogenous DKK3 and DVL-1 was transiently decreased after ICH compared to that in the sham group. Compared to the mice of ICH, exogenous rDKK3 administration reduced the brain water content and affected the neurological functions in ICH mice. Moreover, DKK3 was colocalized with Kremen-1 in microglia. Using a Kremen-1 or DVL-1 siRNA-induced in vivo knockdown approach, we demonstrated that the effects of DKK3 against ICH were mediated , at least partly, by the Kremen-1 and DVL-1 pathways. Conclusions: DKK3 improves the neurological outcomes, potentially by decreasing JNK/AP-1 mediated inflammation, thereby ameliorating the short- and long-term sequelae after ICH.

Recombinant CCL17-dependent CCR4 activation alleviates neuroinflammation and neuronal apoptosis through the PI3K/AKT/Foxo1 signaling pathway after ICH in mice

“…The mass effect of intracerebral hematoma as well as red blood cell debris and degradation products are considered to be key factors leading to early brain injury following ICH [ 7 – 9 ]. As a consequence, a complex inflammatory cascade leads to brain edema, blood–brain barrier (BBB) disruption, neuronal apoptosis in the perihematoma area, and other unfavorable outcomes [ 10 , 11 ]. Therefore, the development of therapies that target anti-inflammatory and anti-apoptotic pathways may be crucial to improving neurological outcomes following ICH.…”

TGR5 activation attenuates neuroinflammation via Pellino3 inhibition of caspase-8/NLRP3 after middle cerebral artery occlusion in rats

“…Brain samples were collected 24 h after MCAO. Western blotting was performed as described previously [35]. The proteins of right hemispheres were extracted by cytoplasmic extraction reagents (Pierce Biotechnology, Rockford, IL, USA).…”

Inhibition of JNK Alleviates Chronic Hypoperfusion-Related Ischemia Induces Oxidative Stress and Brain Degeneration via Nrf2/HO-1 and NF-κB Signaling

“…Several lines of investigation revealed that JNK plays important roles in neuronal inflammation under in vivo conditions. Furthermore, it has reported that increased p-JNK activation mainly disturb the antioxidant defense mechanism and subsequently initiates neuroinflammatory and neurodegenerative cascades [15,36,37]. To evaluate the chronic ischemic condition effects on neuroinflammation, we analyzed the activated p-NF-κB and the expression level of proinflammatory cytokines such as TNF-α, IL-1β, and NOS2 in the ipsilateral cortex and hippocampus of the ischemic brain.…”