Aggravation of experimental allergic encephalomyelitis (EAE) by administration of nitric oxide (NO) synthase inhibitors

Abstract

SUMMARYMacrophages constitute a large proportion of the inflammatory cells that infiltrate the central nervous system (CNS) of animals with EAE. Through the production of inflammatory mediators these infiltrating macrophages can contribute to the regulation of the immune reaction within the CNS, that eventually results in neurological deficits associated with EAE. NO, a free radical produced by macrophages and other cell types. has been pul rorward as such an immune mediator.In the present study we show that macrophages isolated from lhe CNS of Lewis rats with clinical signs of EAE produce elevated amounts of NO. We treated rats, in which EAE was induced, with "+-nitro-r-arginine-methylester or NG-monomethyl-r-arginine, inhibitors of NO synthase, either systemically via intraperitoneal injection, or intracerebrally via a cannula placed in the lateral ventricle. Both treatments resulted in a marked aggravation of clinical signs of EAE. These data point to an important role of NO, produced by infiltrating macrophages, as an immune-suppressor in the disease process during EAE. Upon stimulation, macrophages can secrete a number of molecules that act as inflammatory mediators or tissuedamaging agents, such as the frcc radical NO [5]. In macrophages, NO is synthesized from L-arginine in a reaction catalysed by inducible NO synthase (iNOS) [6].In CNS tissue of Lewis rats in which EAE is induced, iNOS mRNA can be detected either before or coincident with the onset of clinical signs [7]. Furthermore, the production of NO during clinical EAE in the spinal cord of mice with EAE has been demonstrated using electron paramagnetic resonance [S]. In vitra studies have shown that oligodendrocytes, the cells that produce myelin within the CNS, are killed following exposure to N O produced by amoeboid microglia In the present study we show that administration of NO synthase (NOS) inhibitors, either systemically or intraventricularly, aggravates the clinical signs of EAE. Our findings give evidence for an immune-suppressive role for NO, produced by infiltrating macrophages, in the pathogenesis of EAE.

Inflammatory Cytokine Induced Regulation of Superoxide Dismutase 3 Expression by Human Mesenchymal Stem Cells

“…A number of anti-inflammatory pathways are postulated to be important in neuroprotection in the context of neurodegeneration. Specifically, the ROS detoxification pathways are implicated, and a major role for ROS in the pathophysiology of multiple sclerosis has been demonstrated in both pathological and experimental studies [17][18][19][20][21]. ROS include superoxide ions, hydrogen peroxide, nitric oxide and peroxynitrite, all of which are produced as part of the inflammatory response and have a potential role in causing tissue damage in [22], thus limiting the formation of strong neurotoxic oxidants including both the hydroxyl radical and peroxynitrite in the extracellular space.…”

Feedback Regulation of Murine Autoimmunity via Dominant Anti-Inflammatory Effects of Interferon γ

“…Data to support various mechanisms for the anti-inflammatory effects of IFN-␥ have been described, and these include antiproliferative and proapoptotic effects that involve NO production by macrophages or resident microglia (53)(54)(55)(56)(57) or the inhibition of the development of IL-17-producing CD4 ϩ cells that are associated with autoimmunity (38 -41). Our immunohistological analyses indicate no major differences in the numbers of apoptotic cells in the mice in the different groups (data not shown), but this may be due to the greater number of infiltrating cells at the peak of disease in the lower Ag dose groups combined with the susceptibility of infiltrating CD4 ϩ cells to undergo apoptosis in the CNS (58 -60).…”

Selective Vulnerability of Synaptic Signaling and Metabolism to Nitrosative Stress

“…Several groups found that pharmacological inhibitors of iNOS, particularly relatively selective aminoguanidine, potently protect against neurological deficits in EAE models in mice and rats (66,284). However, conflicting data with pharmacological inhibitors of iNOS and the iNOS gene deletion have also been reported (84,132,223). The paradoxical exacerbation of neurological deficits found in these latter studies was explained by the fact that iNOS-derived NO potently suppresses Th1-dependent immune responses, and that inhibition or removal of the enzyme prevents the natural reduction of immune responses (131).…”