A novel alternatively spliced interleukin-1 receptor accessory protein mIL-1RAcP687

Lu, Hsin-Lin; Yang, Chih‐Yung; Chen, Hui‐Chun; Hung, Chih Ming; Chiang, Yu-Chi; Ting, Ling-Pai

doi:10.1016/j.molimm.2007.09.002

Cited by 17 publications

(19 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, these results indicate that the IL-1β inflammatory response in hippocampal neurons depends on AcP and can be attenuated by AcPb, thus supporting the idea that the AcP/AcPb ratio modulates downstream effects of IL-1β signaling. Because both AcP and AcPb are recruited to IL-1R1 in response to IL-1β (20,21), AcPb may attenuate AcP-dependent responses by competing for IL-1R1 binding, thus attenuating IL-1β-induced suppression of BDNF signaling (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…3), and because the IL-1R1-AcP (but not IL-1R1-AcPb) receptor recruits MyD88 via TIR domains (18,20,21) [canonical IL-1β signaling (19)], we hypothesized that the potentiated IL-1β suppression of cLTP in aged synaptosomes is TIR-domaindependent. To block TIR domain signaling, we used TIR mimetics, synthetic compounds that mimic the BB-loop of the TIR domain and specifically block TIR-domain-dependent IL-1β signaling in multiple cell types (47,48) including neurons (49).…”

Section: Nrx1βmentioning

confidence: 99%

“…IL-1β binding to IL-1R1 is followed by AcP recruitment (17), and the ensuing juxtaposition of the Toll/IL-1 receptor (TIR) domains of IL-1R1 and AcP engages the adapter protein MyD88 (18), a fundamental step for activation of downstream effectors of inflammation (e.g., stress kinase p38) (19). In the CNS, however, IL-1β signaling can be additionally mediated by a second accessory protein, AcPb-an alternative splice variant of AcP (20) that is expressed only in neurons (21,22). Although AcP and AcPb have identical extracellular segments, the intracellular C-terminal tail is extended in AcPb, potentially affecting the TIR domain structure (21).…”

mentioning

confidence: 99%

“…Although AcP and AcPb have identical extracellular segments, the intracellular C-terminal tail is extended in AcPb, potentially affecting the TIR domain structure (21). Indeed, although both AcP and AcPb physically interact with IL-1R1 in response to IL-1β, only AcP recruits MyD88, such that AcPb is unable to activate canonical downstream effectors of IL-1β proinflammatory signaling (20,21). As would be predicted, CNS induction of inflammatory cytokines in response to bacterial lipopolysaccharide (LPS) is absent in AcP-deficient mice, but intact in AcPb-deficient mice (21), demonstrating that only AcP activates the proinflammatory response.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus

Prieto

Snigdha

Baglietto‐Vargas

et al. 2015

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

106

121

View full text Add to dashboard Cite

In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1β . In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1β impairment. In hippocampal neuronal cultures, IL-1β increased the expression of the IL-1 receptor type 1 and the accessory coreceptor AcP (proinflammatory), but not of the AcPb (prosurvival) subunit, a reconfiguration that potentiates the responsiveness of neurons to IL-1β. To evaluate whether synapses develop a similar heightened sensitivity to IL-1β with age, we used an assay to track long-term potentiation (LTP) in synaptosomes. We found that IL-1β impairs LTP directly at the synapse and that sensitivity to IL-1β is augmented in aged hippocampal synapses. The increased synaptic sensitivity to IL-1β was due to IL-1 receptor subunit reconfiguration, characterized by a shift in the AcP/AcPb ratio, paralleling our culture data. We suggest that the age-related increase in brain IL-1β levels drives a shift in IL-1 receptor configuration, thus heightening the sensitivity to IL-1β. Accordingly, selective blocking of AcP-dependent signaling with Toll-IL-1 receptor domain peptidomimetics prevented IL-1β-mediated LTP suppression and blocked the memory impairment induced in aged mice by peripheral immune challenge (bacterial lipopolysaccharide). Overall, this study demonstrates that increased AcP signaling, specifically at the synapse, underlies the augmented vulnerability to cognitive impairment by IL-1β that occurs with age.AcP | AcPb | neuroinflammation | receptor sensitivity | LTP

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Nrx1βmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus

Prieto

Snigdha

Baglietto‐Vargas

et al. 2015

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

106

121

View full text Add to dashboard Cite

show abstract

“…Both IL-1RAcP isoforms showed the ability to induce presynaptic differentiation, whereas the abilities to increase the number of dendritic protrusions and to induce Shank2 accumulation were specific for IL-1RAcPb. Because IL-1RAcPb differs from IL-1RAcP only in the C-terminal region (Lu et al, 2008;Smith et al, 2009), it is likely that the C-terminal 240 aa sequence specific for IL-1RAcPb is responsible for the spinogenic activity and the activity to induce postsynaptic differentiation. Among ligand-binding subunits for IL-1 family cytokines, IL-1R1 is a major subunit expressed in neural cells (Yabuuchi et al, 1994;Ericsson et al, 1995;Andre et al, 2005).…”

Section: Discussionmentioning

confidence: 99%