NLRP3 inflammasome inhibitor ameliorates ischemic stroke by reprogramming the phenotype of microglia/macrophage in a murine model of distal middle cerebral artery occlusion

Abstract

Stroke is one of the leading causes of death and disability worldwide. NLRP3 inflammasome has an essential role in the neuropathology of stroke. Recent studies report that shifting the microglial M1 phenotype to the M2 phenotype protects against ischemic stroke. In the present study, the precise effects of Tranilast, a NLPR3 inflammasome inhibitor, on stroke were evaluated. We established a murine model of distal middle cerebral artery occlusion (dMCAO) and administered Tranilast to dMCAO‐induced stroke mice. The NLRP3 level, caspase 1 activity, and infarct volume stroke mice were measured. The sensorimotor function, pro‐inflammatory cytokine production, and M1/M2 marker expression were measured. The M1 phenotype was induced by treatment of BV2 microglia with lipopolysacharide and interferon γ, and these BV‐2 cells were further treated with Tranilast. The expression of CD16 and CD206 was monitored. dMCAO increased the NLRP3 expression and enhanced caspase 1 activity. Tranilast treatment significantly decreased the infarct volume, improved sensorimotor function, and suppressed the production of inflammatory cytokines in stroke mice. Moreover, Tranilast decreased the M1 marker level while promoting the expression of M2 markers. In summary, our findings suggest that Tranilast ameliorates ischemic stroke through stimulating M2 polarization of microglia.

Trends in NLRP3 inflammasome research in ischemic stroke from 2011 to 2022: A bibliometric analysis

“…The second most cited review is a review by Xiong et al 33 published in 2016 that systematically describes the role of microglia/macrophages in neuroinflammation and neurogenesis after stroke, and that NLRP3 plays an important role in glial cell/macrophage polarization. Notably, NLRP3 regulation of glial cell/macrophage polarization in ischemic stroke has been extensively studied in the following years and has become a major hotspot in this field 43–46 . These extensive publications indicate that NLRP3 regulates microglia/macrophage polarization through the nf–κb pathway, specifically by promoting M1 macrophage polarization to exacerbate ischemia–reperfusion injury.…”

“…30 The second most cited review is a review by Xiong et al 33 published in 2016 that systematically describes the role of microglia/macrophages in neuroin- a major hotspot in this field. [43][44][45][46] These extensive publications in- named "#0 nlrp3 inflammasome-mediated neuronal death", "#1 acupuncture", "#2 -induced interleukin-1 secretion", "#3 absence", "#4 natural compound", "#5 adenosine-dependent activation", "#6 telmisartan", "#7 tissue injury", "#8 il-1 production", "#9 acute stroke", and "#10 emerging role". Cluster#0 mainly focuses on NLRP3 inflammasome-mediated neuronal death, indicating the potential role of NLRP3 in neuronal damage.…”

“…Notably, NLRP3 regulation of glial cell/macrophage polarization in ischemic stroke has been extensively studied in the following years and has become a major hotspot in this field. 43 , 44 , 45 , 46 These extensive publications indicate that NLRP3 regulates microglia/macrophage polarization through the nf–κb pathway, specifically by promoting M1 macrophage polarization to exacerbate ischemia–reperfusion injury. Fann et al 32 published an article in Cell Death & Dis in 2013 elucidating NLRP1 and NLRP3 inflammasome meditation was involved in neuronal death during ischemic stroke, where inhibition of NLRP3 and NLRP1 alleviated neuronal death.…”

Activation of LRP1 Ameliorates Cerebral Ischemia/Reperfusion Injury and Cognitive Decline by Suppressing Neuroinflammation and Oxidative Stress through TXNIP/NLRP3 Signaling Pathway in Mice

“…Further research has shown that MiR-423-5p could decrease the polarization of microglia/macrophage cells of the M1 phenotype by inhibiting the mRNA expression of NLRP3 in a spinal cord injury animal model [ 56 ]. Another study also found that Tranilast, an NLRP3 inflammasome inhibitor, could promote the polarization of microglia/macrophage from M1 type to M2 type and ameliorate ischemic stroke by inhibiting the NLRP3/caspase-1 pathway in a murine model of distal middle cerebral artery occlusion [ 57 ]. The activation of the NLRP3 inflammasome triggers the transformation of procaspase-1 to caspase-1, as well as the production and secretion of mature IL-1 β and IL-18.…”

“…The activation was labeled with "+," and the inhibition was labeled with "-." type to M2 type and ameliorate ischemic stroke by inhibiting the NLRP3/caspase-1 pathway in a murine model of distal middle cerebral artery occlusion [57]. The activation of the NLRP3 inflammasome triggers the transformation of procaspase-1 to caspase-1, as well as the production and secretion of mature IL-1β and IL-18.…”