Immunological Mechanism Of GABA_A Receptor Pathway Regulating Atherosclerotic Plaque Stability

Background:Monocyte/macrophage（Mo/MΦ）-mediated innate immune response is the main factor leading to the progression and instability of AS lipid plaques;T lymphocyte subset-mediated adaptive immunity plays an important regulatory role.Recent studies have shown that GABA_Aergic drugs and their mediated GABA_A receptor pathway can effectively regulate the activity of immune/inflammatory cells such as monocytes/macrophages（Mo/MΦ）.However,whether the GABA_A receptor pathway regulates the stability of AS plaques by regulating AS immune/inflammatory responses has not been confirmed.Aim:To study the immunological mechanisms by which the GABA_A receptor pathway regulates the stability of atherosclerotic plaques.Methods and results:ApoE^-/-mice were fed on normal diet or a high fat diet（HFD）for 12 weeks.In ApoE^-/-mice with HFD,we manipulated the endogenous GABA system by injecting GABA_Aergic drugs and PBS intraperitoneally once a day for 12weeks.GABA_Aergic drugs included topiramate,GABA_A-R agonist;picrotoxin,GABA_A-R noncompetitive inhibitor,which blocks the chloride channel;bicuculline,a drug with GABA_A-R competitive inhibitor.Mice were sacrificed after 12 weeks.The results showed that topiramate significantly reduced the area of AS plaque necrosis,decreased macrophage content,and increased systolic smooth muscle content,thereby increasing plaque stability.We further investigated the effects of the GABA_A receptor pathway on innate and adaptive immunity in AS mice.In the innate immune,topiramate inhibited splenic monocytopoiesis,reduced the number of monocytes and Ly6C^high monocytes,and promoted the differentiation of M2 macrophages and the inflammatory cytokines IL-10,TGF-βexpression in AS plaques.,while inhibiting the differentiation of M1 type macrophages and the expression of pro-inflammatory cytokines TNF-α,IL-1β,IL-6,MMP-9.In the adaptive immune response,topiramate can promote the differentiation and function of Th2 by increasing the expression of the Th2-specific signal transduction proteins GATA3.Picrotoxin and bicuculline groups had opposite results.Conclusions:GABA_Aergic drugs can regulate the stability of plaque by regulating AS immune/inflammatory response through the GABA_A receptor pathway.Topiramate,a GABA_A receptor agonist,inhibits splenic monocytopoiesis,inhibits the differentiation of Ly6C^high Mo,promotes the differentiation of macrophages into an anti-inflammatory M2 phenotype,increases its anti-inflammatory function,and promotes the polarization and function of Th2 cells,thereby augmenting plaque stability.