The Microtubule Regulator Stathmin Is an Endogenous Protein Agonist for TLR3

Bsibsi, Malika; Bajramović, Jeffrey J.; Vogt, Monica; Duijvenvoorden, Eveline Van; Baghat, Aabed; Persoon-Deen, Carla; Tielen, Frans; Verbeek, Richard; Huitinga, Inge; Ryffel, Bernhard; Kros, Alexander; Gerritsen, Wouter; Amor, Sandra; Noort, Johannes M. van

doi:10.4049/jimmunol.0902419

Cited by 73 publications

(66 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A reduction in the axonal transport of TRPV1 and GRP, as observed in Tlr3 −/− mice (Supplemental Figure 8), should also contribute to deficits in central sensitization and itch. Of interest, a genome-scale functional screening reveals that the microtubule regulator stathmin is a potential ligand of TLR3 (44). Whether stathmin plays a role in itch by interacting with TLR3 is of great interest.…”

Section: Discussionmentioning

confidence: 99%

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

Liu¹,

Berta²,

Xu³

et al. 2012

J. Clin. Invest.

144

173

View full text Add to dashboard Cite

Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3 −/− mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3 −/− mice but not Tlr7 −/− mice. Consequently, central sensitization-driven pain hypersensitivity, but not acute pain, was impaired in Tlr3 −/− mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3 −/− mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

Liu¹,

Berta²,

Xu³

et al. 2012

J. Clin. Invest.

144

173

View full text Add to dashboard Cite

show abstract

“…Endogenous RNA released by damaged tissue or necrotic cells is able to induce TLR3 expression and signaling (31), whereas the alarmin high-mobility group protein B1 sensitizes TLR3 to the recognition of RNA (32). Interestingly, stathmin, a protein with a regulatory function on microtubule assembly that is up-regulated in brain injury, has been described as a candidate TLR3 agonist, linked to the induction of a neuroprotective gene profile (33). However, no study has assigned a clear protective role to TLR3 endogenous agonists in disease.…”

Section: Discussionmentioning

confidence: 99%

Unexpected protective role for Toll-like receptor 3 in the arterial wall

Cole

Navin

Cross

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

153

146

View full text Add to dashboard Cite

The critical role of Toll-like receptors (TLRs) in mammalian host defense has been extensively explored in recent years. The capacity of about 10 TLRs to recognize conserved patterns on many bacterial and viral pathogens is remarkable. With so few receptors, cross-reactivity with self-tissue components often occurs. Previous studies have frequently assigned detrimental roles to TLRs, in particular to TLR2 and TLR4, in immune and cardiovascular disease. Using human and murine systems, we have investigated the consequence of TLR3 signaling in vascular disease. We compared the responses of human atheroma-derived smooth muscle cells (AthSMC) and control aortic smooth muscle cells (AoSMC) to various TLR ligands. AthSMC exhibited a specific increase in TLR3 expression and TLR3-dependent functional responses. Intriguingly, exposure to dsRNA in vitro and in vivo induced increased expression of both pro- and anti-inflammatory genes in vascular cells and tissues. Therefore, we sought to assess the contribution of TLR3 signaling in vivo in mechanical and hypercholesterolemia-induced arterial injury. Surprisingly, neointima formation in a perivascular collar-induced injury model was reduced by the systemic administration of the dsRNA analog Poly(I:C) in a TLR3-dependent manner. Furthermore, genetic deletion of TLR3 dramatically enhanced the development of elastic lamina damage after collar-induced injury. Accordingly, deficiency of TLR3 accelerated the onset of atherosclerosis in hypercholesterolemic ApoE −/− mice. Collectively, our data describe a protective role for TLR signaling in the vessel wall.

show abstract

“…Moreover, TLRs expressed in neurons were suggested to relate to the inhibition of axonal growth and cell death under noninfectious, nonpathological circumstances, namely development and neurogenesis (27,40,41). In glial cells, the host-derived microtubule regulator stathmin serves as an agonist of TLR3 (46). Besides this, the identity of the endogenous TLR ligands involved in pathways of the CNS is largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Extracellularly Delivered Single-Stranded Viral RNA Causes Neurodegeneration Dependent on TLR7

Lehmann¹,

Rosenberger²,

Krüger³

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Innate immune receptors represent an evolutionarily ancient system that allows organisms to detect and rapidly respond to pathogen- and host-derived factors. TLRs are predominantly expressed in immune cells and mediate such a response. Although this class of pattern recognition receptors is involved in CNS disorders, the knowledge of ligands leading to activation of TLRs and to subsequent CNS damage is limited. We report in this study that ssRNA causes neurodegeneration and neuroinflammation dependent on TLR7 in the CNS. TLR7 is not only expressed in microglia, the major immune cells of the brain, but also in neurons of the CNS. Extracellularly delivered ssRNA40, an oligoribonucleotide derived from HIV and an established ligand of TLR7, induces neuronal cell death dependent on TLR7 and the central adapter molecule MyD88 in vitro. Activation of caspase-3 is involved in neuronal damage mediated by TLR7. This cell-autonomous neuronal cell death induced by ssRNA40 is amplified in the presence of microglia that mount an inflammatory response to ssRNA40 through TLR7. Intrathecal administration of ssRNA40 causes widespread neurodegeneration in wild-type but not in TLR7−/− mice, confirming that neuronal cell death induced by ssRNA40 through TLR7 occurs in vivo. Our results point to a possible mechanism through which extracellularly delivered ssRNA contributes to CNS damage and determine an obligatory role for TLR7 in this pathway.

show abstract

The Microtubule Regulator Stathmin Is an Endogenous Protein Agonist for TLR3

Cited by 73 publications

References 34 publications

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

Unexpected protective role for Toll-like receptor 3 in the arterial wall

Extracellularly Delivered Single-Stranded Viral RNA Causes Neurodegeneration Dependent on TLR7

Contact Info

Product

Resources

About