Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages
Chun-Yun Liu1, Shang-De Guo, Jie-Zhong Yu
1Institute of Brain Science, Department of Neurology, Medical School, Shanxi Datong University, Datong, China.
Abstract:
Although Fasudil has shown therapeutic potential in EAE mice, the mechanism of action are still not fully understood. Here, we examined the immunomodulatory effect of Fasudil on encephalitogenic mononuclear cells (MNCs), and tested the therapeutic potential of Fasudil-treated MNCs in active EAE. Fasudil inhibited expression of CCL20 on T cells and migration of T cells, decreased CD4(+) IFN-γ(+) and CD4(+) IL-17(+) T cells, but increased CD4(+) IL-10(+) and CD4(+) TGF-β(+) T cells. Fasudil reduced expression of CD16/32 and IL-12, while elevating expression of CD206, CD23, and IL-10. Fasudil also decreased levels of iNOS/NO, enhanced levels of Arg-1, and inhibited the TLR-4/NF-κB signaling and TNF-α, shifting M1 macrophage to M2 phenotype. These modulatory effects of Fasudil on T cells and macrophages were not altered by adding autoantigen MOG35-55 to the culture, i.e., autoantigen-independent. Further, we observed that, in vitro, Fasudil inhibited the capacity of encephalitogenic MNCs to adoptively transfer EAE and reduced TLR-4/p-NF-κB/p65 and inflammatory cytokines in spinal cords. Importantly, Fasudil-treated encephalitogenic MNCs exhibited therapeutic potential when injected into actively induced EAE mice. Together, our results not only provide evidence that Fasudil mediates the polarization of macrophages and the regulation of T cells, but also reveal a novel strategy for cell therapy in MS.
Insights
Fasudil treatment modulates T cells and macrophages, shifting them towards an anti-inflammatory profile. Fasudil-treated cells show therapeutic potential in experimental autoimmune encephalomyelitis (EAE), suggesting a novel cell therapy strategy for multiple sclerosis (MS).
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Fasudil's therapeutic potential in experimental autoimmune encephalomyelitis (EAE) is recognized, but its precise mechanism of action remains unclear.
- Understanding Fasudil's immunomodulatory effects is crucial for developing effective cell therapies for autoimmune neurological diseases.
Purpose of the Study:
- To investigate the immunomodulatory effects of Fasudil on encephalitogenic mononuclear cells (MNCs).
- To evaluate the therapeutic potential of Fasudil-treated MNCs in an active EAE model.
- To elucidate the autoantigen-independent mechanisms underlying Fasudil's effects.
Main Methods:
- Assessed Fasudil's impact on T cell populations (IFN-γ, IL-17, IL-10, TGF-β) and macrophage phenotypes (CD16/32, IL-12, CD206, CD23, IL-10, iNOS, Arg-1).
- Investigated the modulation of Toll-like receptor 4 (TLR-4)/nuclear factor-kappa B (NF-κB) signaling and tumor necrosis factor-alpha (TNF-α).
- Evaluated the in vitro capacity of Fasudil-treated MNCs to transfer EAE and their therapeutic efficacy in actively induced EAE mice.
Main Results:
- Fasudil inhibited T cell migration and pro-inflammatory cytokine production (IFN-γ, IL-17) while promoting anti-inflammatory cytokines (IL-10, TGF-β).
- Fasudil induced a shift from M1 to M2 macrophage phenotype by downregulating M1 markers and upregulating M2 markers, and inhibited TLR-4/NF-κB signaling.
- Fasudil-treated MNCs demonstrated reduced capacity to transfer EAE adoptively and exhibited therapeutic potential in EAE mice, independent of autoantigen presence.
Conclusions:
- Fasudil effectively modulates T cells and induces M2 polarization of macrophages in an autoantigen-independent manner.
- Fasudil-treated MNCs possess therapeutic potential for EAE, highlighting a novel cell therapy strategy for multiple sclerosis (MS).
- This study provides mechanistic insights into Fasudil's immunomodulatory actions relevant to autoimmune CNS diseases.
More Related Videos
09:01Flow Cytometric Analysis of Lymphocyte Infiltration in Central Nervous System during Experimental Autoimmune Encephalomyelitis
Published on: November 17, 2020
08:49Simultaneous Isolation of Principal Central Nervous System-Resident Cell Types from Adult Autoimmune Encephalomyelitis Mice
Published on: October 6, 2023
