Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pat...Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.展开更多
We studied the changes of macrophage populations in splenic mononuclear cells of experimental autoimmune ence-phalomyelitis (EAE) mice treated with or without Fasudil. Phenotypic analysis using flow cytometry showed t...We studied the changes of macrophage populations in splenic mononuclear cells of experimental autoimmune ence-phalomyelitis (EAE) mice treated with or without Fasudil. Phenotypic analysis using flow cytometry showed that the levels of TLR4, CD11c and CD40 which represent the type 1 macrophage, were depressed in Fasudil-treated mice. Incontrast, it was observed the expressions of CD200 and CD14 which typify the type 2 macrophage were elevated in Fasudil-treated mice as compared to EAE mice. And we also found that Fasudil at dose of 40 mg/kg alleviated the se-verity of symptom in EAE mice. Based on the evidence that M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth, indicating that polarization and shifting of macrophages into M2 cells may also play key roles in treatment of EAE.展开更多
基金supported by a grant from the Department of Science and Technology of Shanxi Province,China,No.20210302123477(to CL)Datong Bureau of Science and Technology of China,No.2020152(to CL)the Opening Foundation of Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine,No.2022-KF-03(to CL).
文摘Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.
文摘We studied the changes of macrophage populations in splenic mononuclear cells of experimental autoimmune ence-phalomyelitis (EAE) mice treated with or without Fasudil. Phenotypic analysis using flow cytometry showed that the levels of TLR4, CD11c and CD40 which represent the type 1 macrophage, were depressed in Fasudil-treated mice. Incontrast, it was observed the expressions of CD200 and CD14 which typify the type 2 macrophage were elevated in Fasudil-treated mice as compared to EAE mice. And we also found that Fasudil at dose of 40 mg/kg alleviated the se-verity of symptom in EAE mice. Based on the evidence that M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth, indicating that polarization and shifting of macrophages into M2 cells may also play key roles in treatment of EAE.
