TLR-dependent cross talk between human Kupffer cells and NK cells

Tu, Zhengkun; Bozorgzadeh, Adel; Pierce, Robert H.; Kurtis, Jonathan D.; Crispe, Ian Nicholas; Orloff, Mark S.

doi:10.1084/jem.20072195

Cited by 203 publications

(187 citation statements)

References 54 publications

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“…This might explain why NKT cells and NK cells have a poor direct response to CpG-ODN stimulation. Actually, NK cells and NKT cells need help from macrophages or DCs in response to most ligands of TLRs, although NK cells and NKT cells express some TLRs (29,30).…”

Section: Discussionmentioning

confidence: 99%

TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells

Jiang

Sun

Zhou

et al. 2009

The Journal of Immunology

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Increasing evidence suggests that TLRs are involved in the pathogenesis of liver diseases; however, the underlying mechanisms remain obscure. In this study, we found that treatment with CpG-oligodeoxynucleotide (ODN) promoted the accumulation and activation of murine hepatic NKT cells. Additional experiments showed that CpG-ODN preferred to act on CD4+ NKT cells, while having less effect on CD4− NKT cells. The effect of CpG-ODN on liver NKT cells depended on the presence of Kupffer cells and IL-12. Meanwhile, CpG-ODN pretreatment aggravated liver injury and promoted the production of inflammatory cytokines in a Con A-induced fulminant hepatitis model via TLR9 activation. Collectively, our data demonstrate that TLR9 stimulation prefers to promote the accumulation and activation of hepatic CD4+ NKT cells and suggest that TLR9 signaling might be involved in the pathogenesis of human hepatitis.

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Section: Discussionmentioning

confidence: 99%

TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells

Jiang

Sun

Zhou

et al. 2009

The Journal of Immunology

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“…TLR-dependent crosstalk between NK cells and macrophages has already been described in tissue-specific interactions in the liver. TLR-activated liver-resident macrophages have been shown to exert effector function in NK cells, specifically by inducing their activation and IFN-γ production [34]. The ability of IFN-λ1 to modulate TLR-induced crosstalk between macrophages and NK cells could have implications in the enhancement of IFN-γ production by liver NK cells, a critical factor in the inhibition of hepatitis C virus replication and in the response to HBV infection [ [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

IFN‐λ‐mediated IL‐12 production in macrophages induces IFN‐γ production in human NK cells

et al. 2014

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With increasing interest in alternative options to interferon-alpha-based treatments, IFN-λ has shown therapeutic promise in a variety of diseases. Although the antiviral activity of IFN-λ has been extensively studied, there is limited knowledge regarding the immunological functions of IFN-λ and how these differ from those of other classes of IFNs.In this study, we investigated the effects of IFN-λ on primary human NK cells, both in a direct and indirect capacity. We demonstrate that in contrast to interferon-alpha, IFN-λ is unable to directly stimulate NK cells, due to the absence of IFN-λ receptor chain 1 (IFN-λR1) on NK cells. However, IFN-λ, in combination with TLR4 challenge, is able to induce the production of select members of the IL-12 family of cytokines in monocyte-derived macrophages. We further show that through macrophage-mediated IL-12 production, IFN-λ is able to indirectly affect NK cells and ultimately induce IFN-γ production.Keywords: Hepatitis C r IFN-γ r IL-29 r Innate immunity r Macrophages r NK cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells play an important role in the innate immune response, specifically in their ability to recognize and respond to stressed cells, including virus-infected, transformed, and damaged cells. Activated NK cells respond to these stress signals by excretion of cytotoxic factors, including perforin and granzymes, as well as cytokines, such as interferon-γ (IFN-γ) and TNF, that act as a first response to control the source of distress as well as to activate subsequent adaptive immune responses [1,2]. NK cells express an Correspondence: Dr. André Boonstra e-mail: p.a.boonstra@erasmusmc.nl array of activating receptors, such as C-type lectin-like receptors (e.g. NKG2D) and natural cytotoxicity receptors, and inhibiting receptors, C-type lectin-like receptors (e.g. NKG2A) and killer cell immunoglobulin-like receptor. It is currently believed that NK-cell activation or inhibition is governed by a balance of signaling by these receptors, and results after a critical threshold of activation signals exceeds inhibition [3].NK-cell activation ensues after interacting with infected or distressed cells, shifting the balance of inhibitory and activating stimuli delivered via specific surface molecules. These include stressinduced surface markers, including altered MHC expression, as well as soluble factors, of which IL-12 and IL-18 are well described and known triggers of NK-cell effector activity [1,2,4] In line with this, the activity of NK cells can be promoted by exposure to interferon-alpha (IFN-α), e.g. during interaction with IFN-producing activated plasmacytoid DCs leading to enhanced activation and cytolytic activity [9][10][11], and thereby promoting antiviral immunity. In recent years, the type III family of IFNs, comprised IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4, has received increased attention, especially after the discovery of polymorphisms within its gene locus that were a...

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“…hepatocyte damage (65,66). However, the cellular mechanisms underlying the influence of SIGIRR on poly(I:C)-triggered hepatic inflammation remain to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation

Feng

Nie

et al. 2016

The Journal of Immunology

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Single Ig IL-1R–related molecule (SIGIRR, also called IL-1R8 or Toll/IL-1R [TIR]8), a negative regulator for Toll/IL-1R signaling, plays critical roles in innate immunity and various diseases in mammals. However, the occurrence of this molecule in ancient vertebrates and its function in liver homeostasis and disorders remain poorly understood. In this study, we identified a SIGIRR homology from zebrafish (Danio rerio [DrSIGIRR]) by using a number of conserved structural and functional hallmarks to its mammalian counterparts. DrSIGIRR was highly expressed in the liver. Ablation of DrSIGIRR by lentivirus-delivered small interfering RNA in the liver significantly enhanced hepatic inflammation in response to polyinosinic-polycytidylic acid [poly(I:C)] stimulation, as shown by the upregulation of inflammatory cytokines and increased histological disorders. In contrast, depletion of TIR domain–containing adaptor inducing IFN-β (TRIF) or administration of TRIF signaling inhibitor extremely abrogated the poly(I:C)-induced hepatic inflammation. Aided by the zebrafish embryo model, overexpression of DrSIGIRR in vivo significantly inhibited the poly(I:C)- and TRIF-induced NF-κB activations; however, knockdown of DrSIGIRR promoted such activations. Furthermore, pull-down and Duolink in situ proximity ligation assay assays showed that DrSIGIRR can interact with the TRIF protein. Results suggest that DrSIGIRR plays an inhibitory role in TRIF-mediated inflammatory reactions by competitive recruitment of the TRIF adaptor protein from its TLR3/TLR22 receptor. To our knowledge, this study is the first to report a functional SIGIRR homolog that existed in a lower vertebrate. This molecule is essential to establish liver homeostasis under inflammatory stimuli. Overall, the results will enrich the current knowledge about SIGIRR-mediated immunity and disorders in the liver.

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TLR-dependent cross talk between human Kupffer cells and NK cells

Cited by 203 publications

References 54 publications

TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells

TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells

IFN‐λ‐mediated IL‐12 production in macrophages induces IFN‐γ production in human NK cells

Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation

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