Compound A, a Plant Origin Ligand of Glucocorticoid Receptors, Increases Regulatory T Cells and M2 Macrophages to Attenuate Experimental Autoimmune Neuritis with Reduced Side Effects

Abstract

Experimental autoimmune neuritis (EAN) is a helper T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system and serves as the animal model for human inflammatory demyelinating polyneuropathies. Compound A, a plant-derived phenyl aziridine precursor, was reported to activate glucocorticoid receptors to exert transrepression but not transactivation properties. In this study, we investigated the effects of Compound A in EAN rats. Compound A greatly suppressed paraparesis in EAN, even when administrated after the appearance of the first neurological signs. Accumulation of macrophages and lymphocytes, demyelination, and mRNA levels of inflammatory molecules in sciatic nerves of EAN were greatly attenuated by Compound A. In addition, Compound A inhibited progression of neuropathic pain and repressed microglia but not astrocyte activation and IL-1β and TNF-α up-regulation in EAN spinal cords. In EAN sciatic nerves, Compound A treatment increased numbers of anti-inflammatory M2 macrophages. Furthermore, Compound A induced the switch of macrophages from inflammatory M1 type to anti-inflammatory M2 type in vitro. In lymph nodes of EAN rats, Compound A depressed Th1 and Th17 cytokines, but increased Th2 cytokine and Foxp3 expression. An increase of Foxp3+/CD4+ regulatory T cells was seen in peripheral blood of EAN rats following Compound A treatment. In addition, Compound A did not cause a hyperglycemia effect in EAN rats as compared with the immunosuppressive steroid prednisolone. Therefore, our data demonstrated that Compound A could effectively suppress EAN with reduced side effects by attenuating inflammation, suggesting that Compound A could be a potent candidate for treatment of autoimmune neuropathies.

A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

“…In parallel, both DEX and CpdA are able to restore OVA-suppressed Th1 cytokine IFN-g levels, which is in agreement with previous demonstrations for DEX (32). Of note, and in contrast to this model, in a rat model for experimental autoimmune neuritis, which is a Th1 cell-mediated inflammatory demyelinating disease of the peripheral nervous system, CpdA significantly reduced mRNA levels of IFN-g, but increased those of IL-4, suggesting that Th2 cell polarization is favored by CpdA in this context (31). Therefore, even if all T cell subtypes were found to be affected by CpdA in the OVA model, we speculate that CpdA-activated GR may exert a regulatory function on different Th cell phenotypes in other disease models and target tissues, hence fine-tuning equilibrium in the immune response.…”

“…This concept has led to the development of so-called dissociated GR ligands, which lack transactivating properties. CpdA is a fully dissociated nonsteroidal GR agonist that has demonstrated promising anti-inflammatory activity in Th1-driven arthritis and experimental autoimmune encephalomyelitis models (8,10,11,31). To date, there is no report on the effect of CpdA in Th2-dependent models of inflammatory diseases.…”

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

“…Over the last decade, Compound A (CpdA), a natural compound found in the Namibian shrub, was shown to exert strong antiinflammatory actions in vitro and in preclinical studies via GC receptor (GRa)-dependent repression of inflammatory mediators (16)(17)(18)(19)(20). Importantly, these beneficial effects of CpdA were not associated with the typical side effects of GC, which affect the hypothalamic-pituitary-adrenal (HPA) axis (19), levels of insulin (18,19) or glucose (17), or osteoblast differentiation (21) linked to transactivation of GCinducible genes.…”

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

“…17 For the future treatment of PD, it will be interesting to know whether there is an effective strategy to halt the toxic phase of M1 microglia polarization and restore tissue homeostasis by switching the microglia phenotypes or enhancing the beneficial effects of M2 microglia, a notion of which is supported by a recent study in the treatment of experimental autoimmune neuritis disease. 18 Epigenetic is a regulator of gene expression by modifying histone tails or changing DNA methylation. 19 Increasing studies have already shed light on the relationship between 1 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China and 2 Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China *Corresponding author: W Le, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.…”