A Novel Role for Bruton's Tyrosine Kinase in Hepatocyte Growth Factor-mediated Immunoregulation of Dendritic Cells

Singhal, Eshu; Kumar, Prakash; Sen, Pradip

doi:10.1074/jbc.m111.271247

Cited by 37 publications

(53 citation statements)

References 45 publications

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“…The protective actions of HGF in all of these various organ system dysfunctions were tightly associated with the modulation of T cell immune responses, supporting a potent regulation of DC function. Mechanistically, HGF was reported to inhibit DC activation in vitro by disrupting NF-kB signaling via Bruton's tyrosine kinase and a downstream signaling cascade involving sequential activation of the PI3K/AKT pathway and mammalian target of rapamycin (26). In this study, our in vitro and in vivo studies further delineate the molecular events by which HGF confers regulatory functions to DCs.…”

Section: Discussionmentioning

confidence: 57%

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

Benkhoucha

Molnarfi

Dunand-Sauthier

et al. 2014

The Journal of Immunology

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Autoimmune neuroinflammation, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), a prototype for T cell–mediated autoimmunity, is believed to result from immune tolerance dysfunction leading to demyelination and substantial neurodegeneration. We previously showed that CNS-restricted expression of hepatocyte growth factor (HGF), a potent neuroprotective factor, reduced CNS inflammation and clinical deficits associated with EAE. In this study, we demonstrate that systemic HGF treatment ameliorates EAE through the development of tolerogenic dendritic cells (DCs) with high expression levels of glucocorticoid-induced leucine zipper (GILZ), a transcriptional repressor of gene expression and a key endogenous regulator of the inflammatory response. RNA interference–directed neutralization of GILZ expression by DCs suppressed the induction of tolerance caused by HGF. Finally, adoptive transfer of HGF-treated DCs from wild-type but not GILZ gene–deficient mice potently mediated functional recovery in recipient mice with established EAE through effective modulation of autoaggressive T cell responses. Altogether, these results show that by inducing GILZ in DCs, HGF reproduces the mechanism of immune regulation induced by potent immunomodulatory factors such as IL-10, TGF-β1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions.

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Section: Discussionmentioning

confidence: 57%

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

Benkhoucha

Molnarfi

Dunand-Sauthier

et al. 2014

The Journal of Immunology

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“…One potential candidate is Btk, which is known to regulate c-Src activation (11). Therefore, we verified whether crosslinking of TIM-3 activates Btk.…”

Section: Tim-3 Crosslinking Induces Activation Of Btk and C-src In Dcsmentioning

confidence: 94%

“…Membrane proteins from DCs were isolated using the FOCUS Membrane Proteins kit (G-Biosciences). Cell lysates or membrane proteins were immunoprecipitated with anti-TIM-3 Ab (clone 8B.2C12; eBioscience) or rat IgG1,k (clone RTK2071; BioLegend), as described (11), and were analyzed by immunoblotting. Glycosylation of immunoprecipitated TIM-3 was checked on SDS-PAGE gel using a Pro-Q Emerald 488 Glycoprotein Stain Kit (Molecular Probes).…”

Section: Immunoprecipitation Of Tim-3mentioning

confidence: 99%

“…Bone marrow-derived DCs (BMDCs) and splenic DCs (sDCs) were prepared from male or female BALB/c or B6 mice as described (11,13,15).…”

Section: Preparationmentioning

confidence: 99%

“…Previously, we have demonstrated a role for the SH2 domaincontaining signal transducers Bruton's tyrosine kinase (Btk; a member of Tec nonreceptor tyrosine kinase family) and c-Src in immunoregulation of DCs (11,12). However, it remains unknown whether Btk and c-Src participate in TIM-3 signaling.…”

mentioning

confidence: 99%

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Immunoregulation of Dendritic Cells by the Receptor T cell Ig and Mucin Protein-3 via Bruton’s Tyrosine Kinase and c-Src

Maurya

Gujar

Gupta

et al. 2014

The Journal of Immunology

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The receptor T cell Ig and mucin protein-3 (TIM-3) has emerged as an important regulator of innate immune responses. However, whether TIM-3–induced signaling promotes or inhibits the activation and maturation of dendritic cells (DCs) still remains uncertain. In addition, the TIM-3 signaling events involved in this immunoregulatory function are yet to be established. In this article, we report that TIM-3 crosslinking by anti–TIM-3 Ab inhibited DC activation and maturation by blocking the NF-κB pathway. After Ab-mediated crosslinking, TIM-3 became tyrosine phosphorylated, which then sequentially bound and activated the nonreceptor tyrosine kinases Bruton’s tyrosine kinase (Btk) and c-Src. Activation of Btk–c-Src signaling in turn triggered the secretion of some inhibitory factor (or factors) from DCs that inhibited the NF-κB pathway and subsequent activation and maturation of DCs. Silencing of Btk or c-Src abrogated the inhibitory effects of TIM-3 on DCs. These results demonstrate an essential role for Btk–c-Src signaling in TIM-3–induced DC suppression. Thus, in addition to demonstrating an inhibitory role for TIM-3 signaling in DC activation, we define the molecular mechanism by which TIM-3 mediates this effect.

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Bruton’s Tyrosine Kinase (BTK) Beyond B Lymphocytes: A Protein Kinase with Relevance in Innate Immunity

et al. 2015

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A Novel Role for Bruton's Tyrosine Kinase in Hepatocyte Growth Factor-mediated Immunoregulation of Dendritic Cells

Cited by 37 publications

References 45 publications

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

Immunoregulation of Dendritic Cells by the Receptor T cell Ig and Mucin Protein-3 via Bruton’s Tyrosine Kinase and c-Src

Bruton’s Tyrosine Kinase (BTK) Beyond B Lymphocytes: A Protein Kinase with Relevance in Innate Immunity

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