S-nitrosoglutathione a Physiologic Nitric Oxide Carrier Attenuates Experimental Autoimmune Encephalomyelitis

Abstract

S-nitrosoglutathione (GSNO) is a physiological nitric oxide molecule which regulates biological activities of target proteins via s-nitrosylation leading to attenuation of chronic inflammation. In this study we evaluated the therapeutic efficacy of GSNO in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Oral administration of GSNO (0.5 or 1.0 mg/kg) reduced disease progression in chronic models (SJL and C57BL/6) of EAE induced with PLP (139)(140)(141)(142)(143)(144)(145)(146)(147)(148)(149)(150)(151) or MOG peptides, respectively. GSNO attenuated EAE disease by reducing the production of IL17 (from Th i or Th17 cells) and the infiltration of CD4 T cells into the central nervous system without affecting the levels of Th1 (IFNγ) and Th2 (IL4) immune responses. Inhibition of IL17 was observed in T cells under normal as well as Th17 skewed conditions. In vitro studies showed that the phosphorylation of STAT3 and expression of RORγ, key regulators of IL17 signaling, were reduced while phosphorylation of STAT4 or STAT6 and expression of T-bet or GATA3 remained unaffected, suggesting that GSNO preferentially targets Th17 cells. Collectively, GSNO attenuated EAE via modulation of Th17 cells and its effects are independent of Th1 or Th2 cells functions, indicating that it may have therapeutic potential for Th17-mediated autoimmune diseases.

S-Nitrosoglutathione Induces Ciliary Neurotrophic Factor Expression in Astrocytes, Which Has Implications to Protect the Central Nervous System under Pathological Conditions

“…GSNO has recently been reported to regulate various cellular functions (23,38). In addition, earlier we documented that exogenously administered GSNO restores blood brain barrier integrity and attenuates disease severity in experimental autoimmune encephalomyelitis (25,26) and traumatic brain injury (30,31) models. These studies provide evidence that regardless of the excessive expression of inducible nitric-oxide synthase/NO production by activated CNS glial cells in response to inflammatory insult, the exogenously administered GSNO has a tendency to limit the generation of circulating reactive nitrogen species NO/ONOO in vivo (39).…”

“…GSNO) has emerged as a regulator of various intracellular signaling mechanisms via protein S-nitrosylation (23,24). We recently documented that GSNO treatment attenuates experimental autoimmune encephalomyelitis in a murine model of MS via inhibition of mononuclear cell infiltration into the CNS and restoration of blood brain barrier integrity (25,26). GSNO treatment was also protective in other disease models such as stroke (27,28) and traumatic spine and brain injury (29 -31).…”

STAT3 Regulation by S-Nitrosylation: Implication for Inflammatory Disease

“…We previously observed that GSNO treatment inhibited the phosphorylation of STAT3 in T cells (32). Based on the established role of STAT3 in cell cycle progression and proliferation and the reported role of endogenous NO produced by iNOS in cell cycle arrest and inhibition of microglial proliferation (26), we investigated the role of endogenous NO in microglial STAT3 regulation (phosphorylation) and cell proliferation.…”

“…S-nitroso-L-cysteine and S-nitrosoglutathione (GSNO) are the most characterized and abundant endogenous RSNOs synthesized by reaction between NO and cysteine or NO and glutathione (GSH). Recently, these low molecular mass RSNOs have been implicated as a potent anti-inflammatory and antioxidant mediators, vasodilators, and inhibitors of platelet aggregation (6,12,27,32,39). However, the mechanism(s) underlying the role of NO and RSNO in the regulation of microglial proliferation is not understood well at present.…”

Nitric Oxide Storage and Transport in Cells Are Mediated by Glutathione S-Transferase P1-1 and Multidrug Resistance Protein 1 via Dinitrosyl Iron Complexes

“…These results demonstrated that even very low concentrations of the NO donor markedly increased 59 Fe efflux from cells that express MRP1 relative to those that do not. Furthermore, considering that GSNO is a physiologically relevant NO donor (21,22) and that the nitrite levels generated by this agent (10) are similar to, or much less, than those identified in vivo (23), it is apparent the NO levels used herein are within the physiological range (1).…”