Curcumin Ameliorates White Matter Injury after Ischemic Stroke by Inhibiting Microglia/Macrophage Pyroptosis through NF‐κB Suppression and NLRP3 Inflammasome Inhibition

Abstract

NLRP3 inflammasome-mediated pyroptosis is a proinflammatory programmed cell death pathway, which plays a vital role in functional outcomes after stroke. We previously described the beneficial effects of curcumin against stroke-induced neuronal damage through modulating microglial polarization. However, the impact of curcumin on microglial pyroptosis remains unknown. Here, stroke was modeled in mice by middle cerebral artery occlusion (MCAO) for 60 minutes and treated with curcumin (150 mg/kg) intraperitoneally immediately after reperfusion, followed by daily administrations for 7 days. Curcumin ameliorated white matter (WM) lesions and brain tissue loss 21 days poststroke and improved sensorimotor function 3, 10, and 21 days after stroke. Furthermore, curcumin significantly reduced the number of gasdermin D+ (GSDMD+) Iba1+ and caspase-1+Iba1+ microglia/macrophage 21 days after stroke. In vitro, lipopolysaccharide (LPS) with ATP treatment was used to induce pyroptosis in primary microglia. Western blot revealed a decrease in pyroptosis-related proteins, e.g., GSDMD-N, cleaved caspase-1, NLRP3, IL-1β, and IL-18, following in vitro or in vivo curcumin treatment. Mechanistically, both in vivo and in vitro studies confirmed that curcumin inhibited the activation of the NF-κB pathway. NLRP3 knocked down by siRNA transfection markedly increased the inhibitory effects of curcumin on microglial pyroptosis and proinflammatory responses, both in vitro and in vivo. Furthermore, stereotaxic microinjection of AAV-based NLRP3 shRNA significantly improved sensorimotor function and reduced WM lesion following curcumin treatment in MCAO mice. Our study suggested that curcumin reduced stroke-induced WM damage, improved functional outcomes, and attenuated microglial pyroptosis, at least partially, through suppression of the NF-κB/NLRP3 signaling pathway, further supporting curcumin as a potential therapeutic drug for stroke.

Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

“…Microglia are crucial mediators of neuroinflammation and the immune response following central nervous system (CNS) injury [ 26 , 27 ], and are also regarded as the main cell type in which pyroptosis occurs in the CNS [ 9 , 23 , 28 ]. Momentously, NLRP3 inflammasome-mediated GSDMD-triggered pyroptosis in microglia has been implicated in the pathogenesis of subarachnoid hemorrhage [ 29 ], cerebral ischemia/reperfusion injury [ 30 , 31 ] and spinal cord injury [ 23 ]. Although microglia pyroptosis is repeatedly delineated in distinct neuroinflammatory-related diseases, the underlying mechanism of this process remains to be fully elucidated in CVST.…”

Exercise Intervention Modulates Synaptic Plasticity by Inhibiting Excessive Microglial Activation via Exosomes

“…Microglia play a dual role in ischemic brain injury (Ran et al, 2021 ). On the one hand, after cerebral ischemia, microglia respond rapidly to the microenvironment of the brain (Dong et al, 2021 ), change from a resting state (“branching” with pruning synaptic function) to an activated state (“amoeba” with phagocytic function), and migrate to the ischemic region to protect neurons by forming phagocytic fragments (Shi and Pamer, 2011 ).…”

Inflammaging and Brain: Curcumin and Its Beneficial Potential as Regulator of Microglia Activation

“…In addition, attention has recently been paid to the important effect that curcumin can have on the pyroptosis process linked with microglial activation. In a recent study, in fact it was demonstrated that curcumin treatment can attenuate microglial pyroptosis improving white matter integrity as well as functional outcomes, through NF-κB signaling suppression and subsequent NLRP3 inflammasome inhibition in an in vivo model of ischemic stroke pointing out that curcumin has a direct important inhibitory effect on microglial inflammasome activation and pyroptosis [150]. Moreover, in another recent study it was reported that curcumin treatment is protective against cognitive impairments in a rat model of chronic cerebral hypoperfusion combined with diabetes mellitus by suppressing neuroinflammation, apoptosis, and pyroptosis via the regulation of the TREM2/TLR-4/NF-κB pathway in microglia [151].…”