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

Jiang, Wei; Sun, Rui; Zhou, Rongbin; Wei, Haiming; Tian, Zhigang

doi:10.4049/jimmunol.0800973

Cited by 61 publications

(53 citation statements)

References 32 publications

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“…5B). Of note, IL-12 release by activated macrophages promotes T cell activation (8,26), and consistent with this we observed that immunohistochemical analysis showed greater association of F4/80 + macrophages to areas of necrosis in Timp3 2/2 livers (Fig. 5C).…”

Section: Con a Administrationsupporting

confidence: 88%

See 1 more Smart Citation

Stromal TIMP3 Regulates Liver Lymphocyte Populations and Provides Protection against Th1 T Cell-Driven Autoimmune Hepatitis

Murthy

Shao

Defamie

et al. 2012

The Journal of Immunology

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Lymphocyte infiltration into epithelial tissues and proinflammatory cytokine release are key steps in autoimmune disease. Although cell-autonomous roles of lymphocytes are well studied in autoimmunity, much less is understood about the stromal factors that dictate immune cell function. Tissue inhibitor of metalloproteinases 3 (TIMP3) controls systemic cytokine bioavailability and signaling by inhibiting the ectodomain shedding of cytokines and their receptors. The role of TIMP3 in cytokine biology is emerging; however, its contribution to cellular immunology remains unknown. In this study, we show that TIMP3 produced by the hepatic stroma regulates the basal lymphocyte populations in the liver and prevents autoimmune hepatitis. TIMP3 deficiency in mice led to spontaneous accumulation and activation of hepatic CD4+, CD8+, and NKT cells. Treatment with Con A in a model of polyclonal T lymphocyte activation resulted in a greatly enhanced Th1 cytokine response and acute liver failure, which mechanistically depended on TNF signaling. Bone marrow chimeras demonstrated that TIMP3 derived from the stromal rather than hematopoietic compartment provided protection against autoimmunity. Finally, we identified hepatocytes as the major source of Timp3 in a resting liver, whereas significant Timp3 gene transcription was induced by hepatic stellate cells in the inflamed liver. These results uncover metalloproteinase inhibitors as critical stromal factors in regulating cellular immunity during autoimmune hepatitis.

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Section: Con a Administrationsupporting

confidence: 88%

“…The pathologic and protective roles played by macrophages, NK/NKT cells, and the known T cell subsets are well investigated in this model. Currently, the stromal factors responsible for regulating peripheral immune cell homeostasis and cytokine milieu in the liver are largely unknown (5)(6)(7)(8).…”

mentioning

confidence: 99%

Stromal TIMP3 Regulates Liver Lymphocyte Populations and Provides Protection against Th1 T Cell-Driven Autoimmune Hepatitis

Murthy

Shao

Defamie

et al. 2012

The Journal of Immunology

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“…During HCMV infection, monocytes and their derivative cells, which represent the first line of defense, are thought to participate in innate immune response by restricting viral dissemination. Experimental studies indicate that recognition or binding of HCMV particles, which can take place either on the cell surface (Hampton et al, 1991;Peiser et al, 2002;Abate et al, 2004;DeWitte-Orr et al, 2010) or within intracellular endosome (Jiang et al, 2004;Matsushima et al, 2004;Jiang et al, 2009), is an early and potent regulatory signal for the activation of pro-inflammatory cytokines. Monocyte-derived cytokines are essential in triggering T-cell response.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, TLR-9 engagement triggers MYD-88 and NF-κB p65 activation, which regulates gene expression of multiple cytokines, e.g. TNF-α (Tran et al, 2007) and IL-12 (Jiang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Blockade of Lyn kinase upregulates both canonical and non-canonical TLR-3 pathways in THP-1 monocytes exposed to human cytomegalovirus

Yew¹,

Harrison²

2011

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Summary. -Regulation of monocyte response to human cytomegalovirus (HCMV) occurs via activation of receptors that elicit innate antiviral effects and later T-cell responses. Our previous data (Yew et al.., 2010) demonstrated that human monocyte scavenger receptor A type 1 (SR-A1) are required for sensing of HCMV by endosomal toll-like receptors (TLRs)-3 and -9, which in turn induce critical pro-inflammatory cytokines. However, it remains unclear which subcellular molecules associated with SR-A1 lead to downstream activation of TLR-3 and/or TLR-9 signaling pathways. Herein we report that Lyn kinase, associated physically and functionally with SR-A for low density lipoprotein (LDL) recognition, acts as a key SR-A1-induced kinase that plays a critical role in TLR-3/9 signal transduction upon HCMV exposure to THP-1 monocytes. We found that disruption of the SR-A1 signal transduction through molecular inhibition by Lyn kinase oligonucleotides not only blocks the activation of downstream TLR-9 pathway but also alters the downstream TLR-3 pathway. In particular, Lyn kinase oligonucleotides resulted in decreased expression of TLR-9-induced tumor necrosis factor alpha (TNF-α) but strongly upregulated canonical TLR-3-induced interferon beta (IFN-β) and non-canonical TLR-3-induced NF-κB-dependent p35 (35kDa) subunit of interleukin 12 (IL-12p35) gene transcription. Thus, the observed shift away from TNF-α to robust IFN-β and IL-12p35 induction may offer opportunities for therapeutic interventions.Keywords: HCMV; THP-1 monocytes; TLR-3/-9; Lyn kinase; TNF-α; IFN-β; IL-12p35 E-mail: hyew@kumc.edu; fax: +816-983-6515. Abbreviations: HCMV = human cytomegalovirus; IFN-β = interferon beta; IL-12p35 = p35 (35 kDa) subunit of interleukin 12; IRF3 = interferon regulatory factor 3; LDL = low-density lipoproteins; MYD88 = myeloid differentiation primary response gene (88); NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; SR-A1 = scavenger receptor A type 1; TLRs = toll-like receptors; TNF-α = tumor necrosis factor alpha; TRIF = TIR-domaincontaining adapter-inducing IFN-β

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“…112,113 In a preclinical model, CpG administration was possibly linked to enhanced hepatitis pathogenesis induced by concanavalin-A production, but the CpG was not administered by a mucosal route in this case. 114 Another TLR ligand, the TLR3-specific double-stranded RNA oligonucleotide has been shown to modulate local immune responses after i.n administration. 115 In addition, poly(I:C) proved to be an effective adjuvant for an i.n.…”

Section: Mucosal Adjuvantsmentioning

confidence: 99%

Mucosal vaccines

Nizard

Diniz

Roussel

et al. 2014

Human Vaccines & Immunotherapeutics

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

Cited by 61 publications

References 32 publications

Stromal TIMP3 Regulates Liver Lymphocyte Populations and Provides Protection against Th1 T Cell-Driven Autoimmune Hepatitis

Stromal TIMP3 Regulates Liver Lymphocyte Populations and Provides Protection against Th1 T Cell-Driven Autoimmune Hepatitis

Blockade of Lyn kinase upregulates both canonical and non-canonical TLR-3 pathways in THP-1 monocytes exposed to human cytomegalovirus

Mucosal vaccines

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