The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells

Brüstle, Anne; Brenner, Dirk; Knobbe, Christiane B.; Lang, Philipp A.; Virtanen, Carl; Hershenfield, Brian M.; Reardon, Colin; Lacher, Sonja M.; Ruland, Jürgen; Ohashi, Pamela S.; Mak, Tak W.

doi:10.1172/jci63528

Cited by 110 publications

(139 citation statements)

References 60 publications

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“…In addition, proteasomes were shown to contribute to A20 degradation in activated T cells (12), and a similar proteasome-mediated regulation was suggested for CYLD (22). While revising our manuscript, a similar study describing an essential role for MALT1 in EAE was published (23). In that study, MALT1 deficiency was shown to abolish the expression of the Th17 effector cytokines IL-17 and GM-CSF, which are essential for a pathogenic inflammatory response (23).…”

Section: Discussionmentioning

confidence: 72%

“…In that study, MALT1 deficiency was shown to abolish the expression of the Th17 effector cytokines IL-17 and GM-CSF, which are essential for a pathogenic inflammatory response (23). Moreover, the MALT1 substrate RelB was shown to be cleaved and inactivated in wildtype Th17 cells but not in MALT1-deficient Th17 cells, indicating the importance of MALT1 proteolytic activity for the generation of Th17 cells (23). Altogether, these studies indicate an important role for MALT1 proteolytic activity in the pathophysiology of EAE.…”

Section: Discussionmentioning

confidence: 95%

“…While revising our manuscript, a similar study describing an essential role for MALT1 in EAE was published (23). In that study, MALT1 deficiency was shown to abolish the expression of the Th17 effector cytokines IL-17 and GM-CSF, which are essential for a pathogenic inflammatory response (23). Moreover, the MALT1 substrate RelB was shown to be cleaved and inactivated in wildtype Th17 cells but not in MALT1-deficient Th17 cells, indicating the importance of MALT1 proteolytic activity for the generation of Th17 cells (23).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Paracaspase MALT1 Deficiency Protects Mice from Autoimmune-Mediated Demyelination

Guire

Wieghofer

Elton

et al. 2013

The Journal of Immunology

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The paracaspase MALT 1 is a major player in lymphocyte activation and proliferation. MALT1 mediates Ag-induced signaling to the transcription factor NF-κB by functioning both as a scaffold protein and cysteine protease. We studied the role of MALT1 in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. MALT1-knockout mice did not develop any clinical symptoms of EAE. In addition, lymphocyte and macrophage infiltration into the spinal cord was absent in MALT1-knockout mice, as were demyelination and proinflammatory gene expression. Adoptive transfer experiments showed that MALT1 deficiency in splenocytes is sufficient for EAE resistance. Moreover, autoreactive T cell activation was severely impaired in MALT1-deficient T cells, suggesting the inability of MALT1-deficient effector T cells to induce demyelinating inflammation in the CNS. Finally, the MALT1 substrates A20 and CYLD were completely processed in wild-type T cells during EAE, which was partially impaired in MALT1-deficient T cells, suggesting a contribution of MALT1 proteolytic activity in T cell activation and EAE development. Together, our data indicate that MALT1 may be an interesting therapeutic target in the treatment of multiple sclerosis.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Paracaspase MALT1 Deficiency Protects Mice from Autoimmune-Mediated Demyelination

Guire

Wieghofer

Elton

et al. 2013

The Journal of Immunology

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“…Most upstream in the signaling complex, CARMA1 deficiency results in defective Th17 cell differentiation (44). MALT1 is highly expressed in Th17 cells generated in vitro, and MALT1 2/2 Th17 cells produce less IL-17 and GM-CSF (45). Loss of p65/RelA or c-Rel results in impaired Th17 induction in vitro, and c-Rel was shown to interact directly with the Rorc and Il21 promoters (46,47).…”

Section: Discussionmentioning

confidence: 99%

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

Annemann

Wang

Plaza-Sirvent

et al. 2015

The Journal of Immunology

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IL-17–producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A–producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS−/− Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS−/− mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections.

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“…The network analysis revealed multiple potential pathways through which ITGAE and RELB may affect the disease status of OP. In additionally, the RELB is essential for the regulation of IL17A production in GD T cells [23] , while IL17A mediated sRANK ligand elevation is involved in postmenopausal OP [24] . These findings indicates a possible RELB IL17A OP regulatory pathway.…”

Section: Discussionmentioning

confidence: 99%

Possible Linkage Between Osteoporosis and Genes Associated With Type 1 Diabetes Mellitus

2017

Med One

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Background: Previous studies suggested that Type 1 diabetes mellitus (T1DM) is related to an increased risk of osteoporosis (OP) with unknown mechanism. Here, we hypothesized that TIDM and OP present shared molecular basis, and that OP related genes may also play roles for TIDM. Methods:To identify potential OP risk genes from T1DM-gene group, we conducted an integrated analysis using large scale ResNet relation data and gene expression data for T1DM and OP. Disease-gene relation data were acquired from Pathway Studio ResNet Mammalian database. Gene expression profile were acquired from samples of 40 subjects including 20 OP cases and 20 normal controls.Results: Genes linked to T1DM and OP present significant overlap (183 genes, p-value = 2.84E-128). These genes play roles through multiple genetic pathways (enrichment p-value < 8.8e-23 for the top 10 pathways) influencing the pathogenesis of both diseases. A genetic network of 16 genes were identified. T1DM may exert influence on OP these genes. Two T1DM genes, ITGAE and RELB, present significant difference (p-value < 0.0005) between OP cases and controls. Network analysis support the results and reveal strong functional association between OP and these two genes. Conclusion:Results from this study support the hypothesis that complex genetic associations exist between T1DM and OP, and that T1DM related genes should be tested for their potential roles in OP pathogenesis.

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The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells

Cited by 110 publications

References 60 publications

Paracaspase MALT1 Deficiency Protects Mice from Autoimmune-Mediated Demyelination

Paracaspase MALT1 Deficiency Protects Mice from Autoimmune-Mediated Demyelination

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

Possible Linkage Between Osteoporosis and Genes Associated With Type 1 Diabetes Mellitus

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