Increased expression of caspase-1 and interleukin-18 in peripheral blood                 mononuclear cells in patients with multiple sclerosis

Huang, Weihuan; Huang, Ping; Hillert, Jan

doi:10.1191/1352458504ms1071oa

Cited by 112 publications

(79 citation statements)

References 33 publications

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“…In contrast, expression of HLA-DR class II molecule was up-regulated in CD11c high NK cells. Notably, both CD11c and HLA-DR on NK cells were reproducibly induced in vitro in the presence of IL-15 (11) or combination of inflammatory cytokines, known to be increased in the blood of MS (12)(13)(14). Furthermore, we found that the remission state of CD11c high is unstable in comparison to CD11c low , as judged by an increased number of the patients who exacerbated during the 120 days after examining NK cell phenotypes.…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 77%

Differential Expression of CD11c by Peripheral Blood NK Cells Reflects Temporal Activity of Multiple Sclerosis

Aranami

Miyake

Yamamura

2006

The Journal of Immunology

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Multiple sclerosis (MS) is an autoimmune disease, showing a great degree of variance in temporal disease activity. We have recently demonstrated that peripheral blood NK cells biased for secreting IL-5 (NK2 bias) are associated with the remission state of MS. In this study, we report that MS patients in remission differentially express CD11c on NK cell surface (operationally defined as CD11chigh or CD11clow). When we compared CD11chigh or CD11clow patients, the expression of IL-5 and GATA-3 in NK cells supposed to endow a disease-protective NK2 phenotype was observed in CD11clow but not in CD11chigh patients. In contrast, the CD11chigh group showed a higher expression of HLA-DR on NK cells. In vitro studies demonstrated that NK cell stimulatory cytokines such as IL-15 would up-regulate CD11c expression on NK cells. Given previous evidence showing an association between an increased level of proinflammatory cytokines and temporal disease activity in MS, we postulate that inflammatory signals may play a role in inducing the CD11chigh NK cell phenotype. Follow-up of a new cohort of patients showed that 6 of 10 CD11chigh MS patients developed a clinical relapse within 120 days after evaluation, whereas only 2 of 13 CD11clow developed exacerbated disease (p = 0.003). As such, a higher expression of CD11c on NK cells may reflect the temporal activity of MS as well as a loss of regulatory NK2 phenotype, which may allow us to use it as a potential biomarker to monitor the immunological status of MS patients.

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Section: Ultiple Sclerosis (Ms)mentioning

confidence: 77%

Differential Expression of CD11c by Peripheral Blood NK Cells Reflects Temporal Activity of Multiple Sclerosis

Aranami

Miyake

Yamamura

2006

The Journal of Immunology

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“…Caspase-1 has been implicated in both human and mouse neuroinflammation. Caspase-1 levels are significantly increased in peripheral blood mononuclear cells from MS patients (Huang et al, 2004). Moreover, caspase-1 is known to contribute to the pathology of EAE (Furlan et al, 1999;Ahmed et al, 2002).…”

Section: Il-1␤mentioning

confidence: 99%

The Inflammasome Sensor, NLRP3, Regulates CNS Inflammation and Demyelination via Caspase-1 and Interleukin-18

Jha¹,

Srivastava²,

et al. 2010

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Inflammation is increasingly recognized as an important contributor to a host of CNS disorders; however, its regulation in the brain is not well delineated. Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 (NLRP3) is a key component of the inflammasome complex, which also includes ASC (apoptotic speck-containing protein with a card) and procaspase-1. Inflammasome formation can be triggered by membrane P2X 7 R engagement leading to cleavage-induced maturation of caspase-1 and interleukin-1␤ (IL-1␤)/IL-18. This work shows that expression of the Nlrp3 gene was increased Ͼ100-fold in a cuprizone-induced demyelination and neuroinflammation model. Mice lacking the Nlrp3 gene (Nlrp3 Ϫ/Ϫ ) exhibited delayed neuroinflammation, demyelination, and oligodendrocyte loss in this model. These mice also showed reduced demyelination in the experimental autoimmune encephalomyelitis model of neuroinflammation. This outcome is also observed for casp1 Ϫ/Ϫ and IL-18 Ϫ/Ϫ mice, whereas IL-1␤ Ϫ/Ϫ mice were indistinguishable from wild-type controls, indicating that Nlrp3-mediated function is through caspase-1 and IL-18. Additional analyses revealed that, unlike the IL-1␤ Ϫ/Ϫ mice, which have been previously shown to show delayed remyelination, Nlrp3 Ϫ/Ϫ mice did not exhibit delayed remyelination. Interestingly, IL-18Ϫ/Ϫ mice showed enhanced remyelination, thus providing a possible compensatory mechanism for the lack of a remyelination defect in Nlrp3 Ϫ/Ϫ mice. These results suggest that NLRP3 plays an important role in a model of multiple sclerosis by exacerbating CNS inflammation, and this is partly mediated by caspase-1 and IL-18. Additionally, the therapeutic inhibition of IL-18 might decrease demyelination but enhance remyelination, which has broad implications for demyelinating diseases.

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“…We and another group reported that mice lacking genes for Nlrp3 or Asc (Nlrp3 −/− and Asc −/− mice) are resistant to the development of EAE (6,7), suggesting the association of the NLRP3 inflammasome with EAE development. In MS plaques and/or cells from MS patients, the expression of caspase-1, IL-1β, and IL-18 is elevated (8)(9)(10), suggesting the involvement of the NLRP3 inflammasome in MS pathogenicity. However, the mechanism by which the NLRP3 inflammasome induces development of EAE and MS is poorly understood.…”

mentioning

confidence: 99%

NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis

Inoue¹,

Williams

Gunn³

et al. 2012

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

254

230

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The NLRP3 inflammasome is a multiprotein complex consisting of three kinds of proteins, NLRP3, ASC, and pro-caspase-1, and plays a role in sensing pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, the mechanism by which the NLRP3 inflammasome induces EAE is not clear. In this study, we found that the NLRP3 inflammasome played a critical role in inducing T-helper cell migration into the CNS. To gain migratory ability, CD4 + T cells need to be primed by NLRP3 inflammasome-sufficient antigen-presenting cells to up-regulate chemotaxis-related proteins, such as osteopontin, CCR2, and CXCR6. In the presence of the NLRP3 inflammasome, dendritic cells and macrophages also induce chemotactic ability and up-regulate chemotaxis-related proteins, such as α4β1 integrin, CCL7, CCL8, and CXCL16. On the other hand, reduced Th17 cell population size in immunized Nlrp3 −/− and Asc −/− mice is not a determinative factor for their resistance to EAE. As currently applied in clinical interventions of MS, targeting immune cell migration molecules may be an effective approach in treating MS accompanied by NLRP3 inflammasome activation.

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Increased expression of caspase-1 and interleukin-18 in peripheral blood mononuclear cells in patients with multiple sclerosis

Cited by 112 publications

References 33 publications

Differential Expression of CD11c by Peripheral Blood NK Cells Reflects Temporal Activity of Multiple Sclerosis

Differential Expression of CD11c by Peripheral Blood NK Cells Reflects Temporal Activity of Multiple Sclerosis

The Inflammasome Sensor, NLRP3, Regulates CNS Inflammation and Demyelination via Caspase-1 and Interleukin-18

NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis

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