Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: A computational approach

Gong, Jing; Wei, Tian‐Ran; Stark, Robert W.; Jamitzky, Ferdinand; Heckl, Wolfgang M.; Anders, Hans‐Joachim; Lech, Maciej; Rössle, Shaila C.

doi:10.1016/j.jsb.2009.12.007

Cited by 62 publications

(48 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because TIR8 /SIGIRR has been characterized as a negative regulator of TLR7 signaling (34,35), it is possible that the enhanced dermal inflammatory phenotype observed in Tir8/Sigirr 2/2 mice in the Aldara model described above is dependent on this activity. To address this possibility, WT and Tir8/Sigirr 2/2 mice were injected intradermally with rIL-23 or vehicle control daily for up to 7 d. Consistent with previous reports, IL-23 injection induced epidermal thickening in WT mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Imiquimod stimulation of TLR7 on myeloid cells is thought to drive IL-23 expression in the Aldarainduced model of psoriasiform inflammation (10,28). TIR8/SIGIRR has also been described as a negative regulator of TLR7 signaling (34,35) and as such, the observed enhancement of inflammation in Tir8/Sigirr 2/2 mice, could be as a consequence of this activity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Russell

Stefańska

Kubica

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Expression of the orphan receptor Toll IL-1R8/single Ig IL-1–related receptor has been reported to be reduced in the peripheral blood of psoriatic arthritis patients. However whether TIR8/SIGIRR activity plays a specific role in regulating psoriatic inflammation is unknown. We report that Tir8/Sigirr-deficient mice develop more severe psoriatic inflammation in both the chemical (Aldara)- and cytokine (rIL-23)-induced models of psoriasis. Increased disease severity was associated with enhanced infiltration of Vγ4+ γδ T cells that express significantly elevated levels of IL-17A. Critically, we also demonstrate that TIR8/SIGIRR activity directly suppressed innate IL-17A expression by γδ T cells in vitro and in vivo. Importantly, treatment of Tir8/Sigirr−/− mice with an IL-17A neutralization Ab reversed the enhanced disease severity observed in these mice. This study identifies TIR8/SIGIRR as a novel intrinsic negative regulator of innate IL-17A expression and characterizes a novel mechanism involved in the regulation of psoriatic inflammation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Russell

Stefańska

Kubica

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…30 Furthermore, we have recently shown that postischemic cytokine induction in intrarenal dendritic cells is suppressed by the constitutively expressed single immunoglobulin IL-1-related receptor as well as the induction of IFNrelated factor-4, two inhibitors of TLR signaling. [34][35][36] This study identifies extracellular histones as mediators of postischemic and septic AKI. Histones are released from dying tubular epithelial cells and act as DAMPs, which require TLR2 and TLR4 for the induction of proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 97%

Histones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4

Allam

Scherbaum

Darisipudi

et al. 2012

Journal of the American Society of Nephrology

380

369

View full text Add to dashboard Cite

In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-kB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.

show abstract

“…Mice lacking SIGIRR have been shown to be more prone to develop intestinal tumors (39). The mechanism of inhibition of TLRs by SIGIRR remains unclear (40). Although its extracellular immunoglobulin and intracellular TIR domains restrain IL1 signaling by blocking the interaction between IL-1R1 and IL-1RAP, only its TIR domain inhibits TLR signaling (41).…”

Section: Sigirrmentioning

confidence: 99%

“…SIGIRR could either interfere with the organization of TIR domain signalosome (39)(40)(41) or block the translocation of this complex from the receptor (28). It can form heterodimers with TLR4 (40) and decrease the recruitment of MyD88 and IRAK4 to activated TLR4 (41).…”

Section: Sigirrmentioning

confidence: 99%

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Guven-Maiorov

Keskin

Gürsoy

et al. 2015

Biophysical Journal

View full text Add to dashboard Cite

Even though the Toll-like receptor (TLR) pathway is integral to inflammatory defense mechanisms, its excessive signaling may be devastating. Cells have acquired a cascade of strategies to regulate TLR signaling by targeting protein-protein interactions, or ubiquitin chains, but the details of the inhibition mechanisms are still unclear. Here, we provide the structural basis for the regulation of TLR signaling by constructing architectures of protein-protein interactions. Structural data suggest that 1) Toll/IL-1R (TIR) domain-containing regulators (BCAP, SIGIRR, and ST2) interfere with TIR domain signalosome formation; 2) major deubiquitinases such as A20, CYLD, and DUBA prevent association of TRAF6 and TRAF3 with their partners, in addition to removing K63-linked ubiquitin chains that serve as a docking platform for downstream effectors; 3) alternative downstream pathways of TLRs also restrict signaling by competing to bind common partners through shared binding sites. We also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations on the negative regulators and to observe the cellular outcome (whether there is/is not inflammation). Missense mutations that fall on interfaces and nonsense/frameshift mutations that result in truncated negative regulators disrupt the interactions with the targets, thereby enabling constitutive activation of the nuclear factor-kappa B, and contributing to chronic inflammation, autoimmune diseases, and oncogenesis.

show abstract

Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: A computational approach

Cited by 62 publications

References 45 publications

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Histones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Contact Info

Product

Resources

About