PHLDA1 modulates microglial response and NLRP3 inflammasome signaling following experimental subarachnoid hemorrhage

Abstract

Balancing microglia M1/M2 polarization is an effective therapeutic strategy for neuroinflammation after subarachnoid hemorrhage (SAH). Pleckstrin homology-like domain family A member 1 (PHLDA1) has been demonstrated to play a crucial role in immune response. However, the function roles of PHLDA1 in neuroinflammation and microglial polarization after SAH remain unclear. In this study, SAH mouse models were assigned to treat with scramble or PHLDA1 small interfering RNAs (siRNAs). We observed that PHLDA1 was significantly increased and mainly distributed in microglia after SAH. Concomitant with PHLDA1 activation, nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome expression in microglia was also evidently enhanced after SAH. In addition, PHLDA1 siRNA treatment significantly reduced microglia-mediated neuroinflammation by inhibiting M1 microglia and promoting M2 microglia polarization. Meanwhile, PHLDA1 deficiency reduced neuronal apoptosis and improved neurological outcomes after SAH. Further investigation revealed that PHLDA1 blockade suppressed the NLRP3 inflammasome signaling after SAH. In contrast, NLRP3 inflammasome activator nigericin abated the beneficial effects of PHLDA1 deficiency against SAH by promoting microglial polarization to M1 phenotype. In all, we proposed that PHLDA1 blockade might ameliorate SAH-induced brain injury by balancing microglia M1/M2 polarization via suppression of NLRP3 inflammasome signaling. Targeting PHLDA1 might be a feasible strategy for treating SAH.

Dental pulp mesenchymal stem cell-derived exosomes inhibit neuroinflammation and microglial pyroptosis in subarachnoid hemorrhage via the miRNA-197-3p/Foxo3 axis

“…Upregulation of phosphorylated TAK1 promotes NF-κB p65 nuclear translocation and NLRP3 upregulation, inducing neuronal pyroptosis [64]. Additionally, LDC7559, a novel GSDMD inhibitor, inhibited neuronal pyroptosis post-SAH [65]. However, several studies have reported mechanisms underlying NLRP3-mediated microglial pyroptosis in SAH.…”

Role of gasdermin family proteins in cancers (Review)

“…NLRP3 and caspase inhibitors have been explored for the treatment of neurodegenerative diseases by targeting overactivated pyroptosis and have shown certain effects (44,118,119). Recently, LDC7559, a newly developed selective GSDMD inhibitor, was reported to promote brain functional recovery by inhibiting over-activated pyroptosis by directly blocking the GSDMD-N-terminus (120,121). However, whether these inhibitors may also be used for cancer treatment remains to be investigated.…”

Role of NLRP3 inflammasome in central nervous system diseases

“…Unfortunately, this study did not deeply explore the bidirectional regulation and causal relationship between intestinal microflora, NLRP3 inflammasome and cerebral hemorrhage after ICH. In addition, silymarin, atorvastatin, baicalein, mst4, h2s, a68930induced activation of drd1, fimasartan, p2y6 receptor activation, histone deacetylation 10, verbascoside, verapamil, cordycepin, dexmedetomidine, andrographolide and others can directly or indirectly inhibit NLRP3 activation to reduce nerve inflammation, improve secondary brain injury after ICH, and play a neuroprotective role [83][84][85][86][87][88][89][90][91][92][93][94][95][96].…”

“…INT-777, a TGR5 agonist, can inhibit the NLRP3 activation through TGR5/cAMP/ PKA signaling pathway, alleviate acute cerebral edema and neuroinflammation, and hippocampal neuronal degeneration 28 days after SAH [89]. Inhibition of NLRP3 activation by PHLDA1 can induce M2 polarization of microglia after SAH and improve neuroinflammation and neuronal apoptosis [90]. Takinib can reduce oxidative damage, neuroinflammation, brain edema and neuronal apoptosis after SAH by inhibiting TAK1-ROS-NLRP3 signaling pathway, and improve neurological deficit [91].…”