Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia

Abstract

IL-12 has long been considered important in the pathogenesis of multiple sclerosis. However, evidence from recent studies strongly supports the critical role of IL-12-related proinflammatory cytokine IL-23, but not IL-12, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of this disease. The role of IL-23 in the CNS immunity of multiple sclerosis patients has not been elucidated; nor is it known whether human microglia produce this cytokine. In this study we investigated the expression of IL-23p19 and p40, with its key subunit p19 as the focus, in histologically characterized CNS specimens from multiple sclerosis and control cases using in situ hybridization and immunohistochemistry. A significant increase in mRNA expression and protein production of both subunits of IL-23 was found in lesion tissues compared with non-lesion tissues. Double staining showed that activated macrophages/microglia were an important source of IL-23p19 in active and chronic active multiple sclerosis lesions. We also detected IL-23p19 expression in mature dendritic cells which were preferentially located in the perivascular cuff of active lesions. The finding that human microglia produce IL-23 was further confirmed by the inducible production of IL-23p19 and p40 in cultured human microglia in vitro upon different Toll-like receptor stimulations. Taken together, these findings on the expression of IL-23p19 in multiple sclerosis lesions may lead to a better understanding of the events culminating in human multiple sclerosis.

Interleukin-17 Production in Central Nervous System-Infiltrating T Cells and Glial Cells Is Associated with Active Disease in Multiple Sclerosis

“…They include the cytokine IL-23, which is expressed by dendritic cells and macrophages/microglia cells in MS lesions. 35 In addition, after CNS injury or inflammation, astrocytes respond with hypertrophy, hyperplasia, and increased production of IL-6 and IL-1␤, which are also found to be increased in MS lesions. 36,37 In combination with additional inflammatory cytokines released by macrophages/microglia (IL-6, IL-1␤, and tumor necrosis factor-␣), they could not only divert the differentiation of activated or naïve T cells entering the inflamed CNS into an IL-17-producing phenotype but could also alter the astrocytes themselves in an autocrine/paracrine manner in the active MS lesions.…”

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

“…More interesting, Act-1 abrogation from microglia/macrophage or endothelial cells did not show any difference (Kang Z 2010) .This points out not only the main target of IL-17 activity, but also the importance of the CNS resident cells as astrocytes in the pathogenesis of EAE. Moreover, using astrocytes cultures, researchers demonstrated that these cells are able to induce Th1 and Th17 cells (Li Y 2007).…”

Evaluation of Bone Marrow- and Brain-Derived Neural Stem Cells in Therapy of Central Nervous System Autoimmunity

“…[1][2][3] MS begins when peripherally activated myelin-reactive T cells infiltrate into the CNS, followed closely by other immune cells, including naïve myelin-reactive T cells, polyclonal T cells, macrophages, dendritic cells, B cells, and neutrophils. [1][2][3][4] Once in the CNS, myelin-reactive T cells are presented with myelin antigens, and become activated/reactivated, thereby triggering an immunological cascade that results in myelin damage. This process occurs in the initial phase of the disease and continues to some extent during the chronic and relapse phases.…”