Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages

Abstract

Keywords: Experimental autoimmune encephalomyelitis r Fasudil r Macrophage polarization r Rho kinase inhibitor r T-cell regulation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMultiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), which is characterized by chronicCorrespondence: Prof. Bao-Guo Xiao e-mail: bgxiao@shmu.edu.cn inflammation, myelin destruction, axonal loss, and neurological disability [1]. The exact cause of MS is still unknown, but the pathogenesis of MS/experimental autoimmune encephalomyelitis (EAE) is known to involve the following: (i) myelin-specific T cells are initially activated, (ii) activated T cells migrate across the blood-brain barrier (BBB) and infiltrate the CNS parenchyma, (iii) infiltrated T cells produce proinflammatory cytokines, which [6]. Despite these detrimental roles of macrophages within the injured CNS, many studies have also reported beneficial roles of macrophages. Treatment with M2 macrophages resulted in an attenuation of EAE progression [7,8].Given that polarized macrophages are reversible in a well-defined microenvironment, the polarization of M1 cells and M2 cells has become a new therapeutic target for MS. Rho-kinase (ROCK), a serine/threonine kinase, plays the role of molecular switch by regulating cell migration, proliferation, and survival [7]. A series of studies have demonstrated that the expression and/or activity of ROCK were increased in different EAE models [9][10][11][12][13] due to the release of inhibitory molecules (such as Nogo A, MAG, and Omgp) from damaged CNS tissues that activated the Rho/ROCK signal transduction pathway [14]. Inhibition of ROCK resulted in accelerated regeneration and enhanced functional recovery, which has also proved to be efficacious in animal models of stroke [15], MS [9-13], ALS [16], Alzheimer's disease [17], and Parkinson's diseases [18,19]. ROCK is therefore considered a promising drug target for preventing neurodegeneration and stimulating neuroregeneration in several neurological diseases [20]. Previous investigations from our group and other labs have indicated that the ROCK inhibitor Fasudil ameliorates the clinical severity of EAE in different models and at different stages [9][10][11]13], accompanied by reduced demyelination and inhibition of neuroinflammation [9,10,12,13]. Mechanisms underlying the therapeutic potential of Fasudil in EAE models include (i) downregulation of Th17 and Th1 T cells [9,10], (ii) protection of BBB and blood-spinal cord barrier integrity [11], (iii) inhibition of TLR-4 and p-NF-κB/p65 inflammatory axis [12], and (iv) shift from M1 to M2 macrophages [13]. Although there are several publications describing the therapeutic effects and immunological changes of Fasudil in EAE models, little is known about its immunomodulatory effect on macrophages and T cells. In addition, given that Fasudil has certain limitations in clinical practice, including a relatively narrow safety window, it...

Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance

“…Furthermore, CD44 expression, which melatonin augmented in Tregs, is known to increase IL-10 expression (Bollyky et al, 2009(Bollyky et al, , 2007. Interestingly, our data suggest a non-antigen dependent production of IL-10 by the in vitro cultured CNS mononuclear cells from melatonin treated mice, suggesting alternative sources of IL-10 other than Treg cells, such as B regulatory cells, implicated in suppression of the early stages of EAE (Fillatreau et al, 2002), or M2 macrophages/microglia (Liu et al, 2015).…”

Rho kinase II interference by small hairpin RNA ameliorates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice

“…The neuro-protective effects of fasudil, a ROCK inhibitor (4,25) may be partly mediated through inhibiting neuro-inflammation. In a previous study, fasudil exhibited therapeutic potential in experimental autoimmune encephalomyelitis (26). Fasudil rebalanced T helper 17 and regulatory T cells, induced microglial polarization towards M2, and inhibited inflammatory responses (26).…”

“…In a previous study, fasudil exhibited therapeutic potential in experimental autoimmune encephalomyelitis (26). Fasudil rebalanced T helper 17 and regulatory T cells, induced microglial polarization towards M2, and inhibited inflammatory responses (26). …”

LINGO-1-Fc-Transduced Neural Stem Cells Are Effective Therapy for Chronic Stage Experimental Autoimmune Encephalomyelitis

“…Slides were assessed and scored in a blinded fashion for inflammation [36]: 0, none; 1, a few inflammatory cells; 2, organization of perivascular infiltrates; and 3, abundant perivascular cuffing with extension into the adjacent tissue. For quantification of demyelination, total white matter was manually outlined, and the area (%) of demyelination was calculated by Image-Pro Plus software [37]. For toluidine staining, spinal cords were dissected and incubated in 2 % paraformaldehyde plus 2.5 % glutaraldehyde overnight.…”