Murine B Cell Response to TLR7 Ligands Depends on an IFN-β Feedback Loop

Green, Nathaniel M.; Laws, Amy; Kiefer, Kerstin; Busconi, Liliana; Kim, You-Me; Brinkmann, Melanie M.; Trail, Erin Hodges; Yasuda, Kei; Christensen, Sean R.; Shlomchik, Mark J.; Vogel, Stefanie N.; Connor, John H.; Ploegh, Hidde L.; Eilat, Dan; Rifkin, Ian R.; Seventer, Jean Maguire van; Marshak‐Rothstein, Ann

doi:10.4049/jimmunol.0803899

Cited by 108 publications

(109 citation statements)

References 50 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…It has been shown that IFNAR signals play important roles in regulating TLR7 responses in both human and mouse B cells, contributing to the roles played by TLR7 in both normal immunity and autoimmunity (12)(13)(14). In this study, we demonstrated a novel role for the IFNAR in regulating TLR7 responses in B cells.…”

Section: Discussionmentioning

confidence: 49%

“…TLR expression (35). In B cells, IFNAR signals are shown to induce increased TLR7 expression (14). However, our findings show that TLR7 expression was not decreased in tolerant B cells.…”

Section: Discussionmentioning

confidence: 53%

“…B cells coordinate signals from a variety of receptors essential for appropriate regulation of B cell responses (26). TLR7-mediated proliferation and IL-6 production by both human and murine B cells are dependent on signals through the IFNAR (12,14). Because BCR signals restore optimum B cell activation in TLR7-tolerant B cells (25), we hypothesized that TLR7 tolerance may reflect defective type I IFN production, and BCR-mediated reversal of TLR7 tolerance may act by restoring IFNAR signaling in tolerant B cells.…”

Section: Resultsmentioning

confidence: 99%

“…Type I IFN also enhances memory B cell responsiveness to TLR7-mediated plasmablast differentiation (12,13). In addition, TLR7-mediated B cell proliferation, cytokine production, and costimulatory molecule expression are defective in IFNAR 2/2 mice (14). Many synthetic TLR7 ligands are currently under investigation as vaccine adjuvants (15) and antitumor agents (16), and type I IFN also enhances adjuvant activity of such ligands (17).…”

mentioning

confidence: 99%

“…TLR7 tolerance can be prevented and overcome by providing prior or simultaneous signals through the BCR (25). Because certain B cell TLR7 responses are regulated by IFNAR signals (12,14), we investigated the role of IFNAR-mediated regulation of TLR7 tolerance in B cells. We found that BCR-mediated signals that mitigate against TLR7 tolerance were not dependent on type I IFN.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Poovassery

Bishop

2012

The Journal of Immunology

View full text Add to dashboard Cite

Toll-like receptor 7 (TLR7) signals to B cells are critically involved in the innate immune response to microbes, as well as pathogenesis of autoimmune diseases, but the molecular mechanisms that normally regulate these responses are incompletely understood. We previously reported that repeated stimulation through TLR7 induces a state of hyporesponsiveness (TLR tolerance) in both human and mouse B cells, characterized by marked inhibition of particular signaling pathways. BCR signals prevent and overcome TLR7 tolerance. Because optimal responses to TLR7 in B cells require type I IFN, we investigated whether BCR-mediated effects on TLR7 tolerance are mediated by type I IFN receptor (IFNAR) signals. Surprisingly, although BCR-mediated reversal of TLR7 tolerance was IFNAR independent, IFNAR signals alone also blocked TLR7 tolerance, despite enhancing TLR7 expression. Both BCR and IFNAR signals restored the phosphorylation of the transcriptional regulator c-Jun, but only BCR signals blocked the tolerance-mediated inhibition of JNK. Both BCR and IFNAR-mediated regulation was dependent on activation of the PI3K/Akt/mammalian target of rapamycin signaling pathway, indicating a central role for this axis in integrating TLR7, BCR, and IFNAR signals in B cells. These new findings reveal distinct and overlapping signaling mechanisms used by BCR and IFNAR in the regulation of TLR7 tolerance and activation.

show abstract

Section: Discussionmentioning

confidence: 49%

“…TLR expression (35). In B cells, IFNAR signals are shown to induce increased TLR7 expression (14). However, our findings show that TLR7 expression was not decreased in tolerant B cells.…”

Section: Discussionmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Poovassery

Bishop

2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

Bone Marrow–Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence‐Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein–Interferon‐β Feedback Loop

Gao

Bird

Meednu

et al. 2017

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective BMSCs create a special microenvironment for hematopoiesis and immunity and also display robust immunomodulatory properties which are impaired in SLE. This study was undertaken to define the mechanisms of defects in human SLE BMSCs. Methods Patients fulfilling SLE classification criteria and healthy controls were recruited under an Institutional Review Board approved protocol (n=6 each). BMSCs were isolated with low density Ficoll/Hypaque. BMSCs were verified by flow cytometry and studied using immunocytochemistry, real-time PCR, western blotting, comet assay, beta-galactosidase assay, and RNA interference. Results SLE BMSCs have a senescent phenotype characterized by reduced proliferation rate, increased production of reactive oxygen species (ROS), increased DNA damage and repair, increased expression of p53 and p16 which block the cell cycle, and altered cytokine production (increased pro-inflammatory cytokine and decreased immunomodulatory cytokine production). Moreover, SLE BMSCs have a 5 fold increase in IFNβ (p<0.05) and increased IFNβ-induced mRNAs including mRNA for the intracellular nucleic acid sensing adaptor protein MAVS whose expression was highly correlated with IFNβ levels (r > 0.9, p < 0.01). Since MAVS is known to induce IFNβ production, we hypothesized a positive feedback loop between MAVS and IFNβ. Strikingly, silencing MAVS markedly decreased IFNβ, p53, and p16 protein levels and expression of mRNAs for pro-inflammatory cytokines. Conclusions This study demonstrates a novel pathway for elevated IFNβ signaling in SLE that is not dependent on stimulation by immune complexes but rather is cell-intrinsic and critically mediated by IFNβ and MAVS, implicating new pathways as potential therapeutic targets.

show abstract

Lupus Interference With B Cell Tolerance Across the Developmental Continuum

Pemberton¹,

Jackson

2023

Arthritis & Rheumatology

View full text Add to dashboard Cite

Murine B Cell Response to TLR7 Ligands Depends on an IFN-β Feedback Loop

Cited by 108 publications

References 50 publications

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Bone Marrow–Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence‐Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein–Interferon‐β Feedback Loop

Lupus Interference With B Cell Tolerance Across the Developmental Continuum

Contact Info

Product

Resources

About