Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage

Abstract

Inducible nitric oxide synthase (iNOS) is an enzyme that produces nitric oxide (NO) and is thought to contribute to the pathogenesis of multiple sclerosis (MS). The extent of iNOS expression was examined using laser scanning confocal microscopy of 13 chronic active plaques from seven MS patients displaying both acute demyelination and active inflammation. iNOS expression in these plaques was substantial and diverse in cellular distribution. Expression of iNOS was observed in ependymal cells located in periventricular lesions, inflammatory cells, and occasionally in astrocytes. iNOS was found in microglial/macrophage cells that expressed CD64, the high affinity Fc gamma receptor associated with cells that have phagocytic function and participate in antibody-dependent cellular cytotoxicity (ADCC). Scavenger microglial/macrophage cells that expressed the marker CD14 were also present and may express iNOS. The markers for myelin damage, nitrotyrosine (an index of iNOS mediated damage via peroxynitrite formation), along with MBP fragments, were also observed associated with iNOS in MS plaques. Together, these findings support a central role for iNOS in the pathogenesis of multiple sclerosis.