Kinetics of Proinflammatory Monocytes in a Model of Multiple Sclerosis and Its Perturbation by Laquinimod

Mishra, Manoj Kumar; Wang, Janet; Silva, Claudia; Mack, Mathias; Yong, V. Wee

doi:10.1016/j.ajpath.2012.05.011

Cited by 75 publications

(68 citation statements)

References 53 publications

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“…The initiation and progression of EAE are associated with infiltration of immune cells into the CNS and subsequent immune responses between the adaptive and innate immune systems (54). CCR2 + Ly6C hi monocytes are among the earliest monocytes to infiltrate the CNS and are crucial for the development of EAE (55)(56)(57)(58). Therefore, the decrease of CCR2…”

Section: Discussionmentioning

confidence: 99%

Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

Jiang

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The nonneural cholinergic system of immune cells is pivotal for the maintenance of immunological homeostasis. Here we demonstrate the expression of choline acetyltransferase (ChAT) and cholinergic enzymes in murine natural killer (NK) cells. Ly6Chi monocytes directly via the disruption of tolerance and inhibited the production of proinflammatory cytokines. Interestingly, ChAT + NK cells and CCR2 + Ly6C hi monocytes formed immune synapses; moreover, the impact of ChAT + NK cells was mediated by α7-nicotinic acetylcholine receptors. Finally, the NK cell cholinergic system up-regulated in response to autoimmune activation in multiple sclerosis, perhaps reflecting the severity of disease. Therefore, this study extends our understanding of the nonneural cholinergic system and the protective immune effect of acetylcholine-producing NK cells in autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

Jiang

Han

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Chemokine receptors can be targeted well by small molecular weight drugs; some of these are currently under investigation, but their value for treating kidney disease is unclear at present. Finally, some immunosuppressive drugs, such as laquinimod, have been shown to reduce chemokine secretion and immune cell infiltration in other tissues and may be of use in nephritis (109).…”

Section: Preventing Dcs and Macrophage Recruitmentmentioning

confidence: 99%

Dendritic Cells and Macrophages

Weisheit¹,

Engel

Kurts

2015

Clinical Journal of the American Society of Nephrology

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The mononuclear phagocytes (dendritic cells and macrophages) are closely related immune cells with central roles in anti-infectious defense and maintenance of organ integrity. The canonical function of dendritic cells is the activation of T cells, whereas macrophages remove apoptotic cells and microbes by phagocytosis. In the kidney, these cell types form an intricate system of mononuclear phagocytes that surveys against injury and infection and contributes to organ homeostasis and tissue repair but may also promote progression of CKD. This review summarizes the general functions and classification of dendritic cells and macrophages in the immune system and recapitulates why overlapping definitions and historically separate research have created controversy about their tasks. Their roles in acute kidney disease, CKD, and renal transplantation are described, and therapeutic strategy to modify these cells for therapeutic purposes is discussed.

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“…It was reported that treatment of mice with laquinimod is associated with alterations in the frequency of myeloid subpopulations that included a reduction in CD4 + DCs. Laquinimod treatment also promoted the development of anti-inflammatory type II monocytes and DCs (6,7,9), which are likely associated with its immunomodulatory activities. These activities include reduced production of proinflammatory cytokines such as IL-17, reduced migration of lymphocytes (4, 7), augmentation of regulatory T-cell numbers (5,7), and production of brain-derived neurotrophic factor (5,8).…”

mentioning

confidence: 99%

“…The influence of laquinimod on the immune system was studied in experimental autoimmune encephalomyelitis (EAE) (4)(5)(6)(7)(8)(9)(10)(11)(12), an autoimmune disease mediated by proinflammatory myelinreactive lymphocytes that cause CNS inflammation leading to demyelination and axonal loss. Laquinimod has also been effective in the treatment of other models of autoimmune diseases, specifically experimental autoimmune neuritis (13,14), lupus nephritis (15), and colitis (16).…”

mentioning

confidence: 99%

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

Kaye

Piryatinsky

Birnberg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

114

102

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Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR −/− mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.aryl hydrocarbon receptor | EAE | laquinimod L aquinimod is an oral drug that is currently in late-stage clinical development for the treatment of relapsing remitting multiple sclerosis (RRMS), primary progressive MS, and Huntington's disease. Current knowledge indicates that laquinimod exerts activities both on the peripheral immune system and within the CNS. Laquinimod, at the 0.6-mg/d dose, has demonstrated efficacy in phase II and III MS clinical trials, in which it reduced relapse rate, disability progression, development of new and active MRI lesions, and brain atrophy (1-3). The clinical efficacy profile of laquinimod is characterized by a dissociation of the moderate magnitude of the effect on relapse reduction and its associated inflammatory MRI findings and the disproportionally large effect on disability progression. Such an efficacy profile in patients with RRMS may relate to a distinctive intracerebral activity potentially mediated via changes in CNS resident cell populations, potentially astrocytes and microglia.

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Kinetics of Proinflammatory Monocytes in a Model of Multiple Sclerosis and Its Perturbation by Laquinimod

Cited by 75 publications

References 53 publications

Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

Dendritic Cells and Macrophages

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

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