Dataset Information

Primary cilia modulate TLR4-mediated inflammatory responses in hippocampal neurons.

ABSTRACT:

Background

The primary cilium is an organelle that can act as a master regulator of cellular signaling. Despite the presence of primary cilia in hippocampal neurons, their function is not fully understood. Recent studies have demonstrated that the primary cilium influences interleukin (IL)-1?-induced NF-?B signaling, ultimately mediating the inflammatory response. We, therefore, investigated ciliary function and NF-?B signaling in lipopolysaccharide (LPS)-induced neuroinflammation in conjunction with ciliary length analysis.

Methods

Since TLR4/NF-?B signaling is a well-known inflammatory pathway, we measured ciliary length and inflammatory mediators in wild type (WT) and TLR4^-/- mice injected with LPS. Next, to exclude the effects of microglial TLR4, we examined the ciliary length, ciliary components, inflammatory cytokine, and mediators in HT22 hippocampal neuronal cells.

Results

Primary ciliary length decreased in hippocampal pyramidal neurons after intracerebroventricular injection of LPS in WT mice, whereas it increased in TLR4^-/- mice. LPS treatment decreased primary ciliary length, activated NF-?B signaling, and increased Cox2 and iNOS levels in HT22 hippocampal neurons. In contrast, silencing Kif3a, a key protein component of cilia, increased ARL13B ciliary protein levels and suppressed NF-?B signaling and expression of inflammatory mediators.

Conclusions

These data suggest that LPS-induced NF-?B signaling and inflammatory mediator expression are modulated by cilia and that the blockade of primary cilium formation by Kif3a siRNA regulates TLR4-induced NF-?B signaling. We propose that primary cilia are critical for regulating NF-?B signaling events in neuroinflammation and in the innate immune response.

SUBMITTER: Baek H

PROVIDER: S-EPMC5606072 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Primary cilia modulate TLR4-mediated inflammatory responses in hippocampal neurons.

Baek Hyunjung H Shin Hyo Jung HJ Kim Jwa-Jin JJ Shin Nara N Kim Sena S Yi Min-Hee MH Zhang Enji E Hong Jinpyo J Kang Joon Won JW Kim Yonghyun Y Kim Cuk-Seong CS Kim Dong Woon DW

Journal of neuroinflammation 20170919 1

<h4>Background</h4>The primary cilium is an organelle that can act as a master regulator of cellular signaling. Despite the presence of primary cilia in hippocampal neurons, their function is not fully understood. Recent studies have demonstrated that the primary cilium influences interleukin (IL)-1β-induced NF-κB signaling, ultimately mediating the inflammatory response. We, therefore, investigated ciliary function and NF-κB signaling in lipopolysaccharide (LPS)-induced neuroinflammation in con ...[more]

PMID: 28927423

Similar Datasets

Project description:Cilia are sensory organelles that project from the surface of almost all cells. Nephronophthisis (NPH) and NPH-related ciliopathies are degenerative genetic diseases caused by mutation of cilia-associated genes. These kidney disorders are characterized by progressive loss of functional tubular epithelial cells which is associated with inflammation, progressive fibrosis, and cyst formation, ultimately leading to end-stage renal disease. However, disease mechanisms remain poorly understood. Here, we show that targeted deletion of cilia in renal epithelial cells enhanced susceptibility to necroptotic cell death under inflammatory conditions. Treatment of non-ciliated cells with tumor necrosis factor (TNF) α and the SMAC mimetic birinapant resulted in Ripk1-dependent cell death, while viability of ciliated cells was almost not affected. Cell death could be enhanced and shifted toward necroptosis by the caspase inhibitor emricasan, which could be blocked by inhibitors of Ripk1 and Ripk3. Moreover, combined treatment of ciliated and non-ciliated cells with TNFα and cycloheximide induced a cell death response that could be partially rescued with emricasan in ciliated cells. In contrast, non-ciliated cells responded with pronounced cell death that was blocked by necroptosis inhibitors. Consistently, combined treatment with interferon-γ and emricasan induced cell death only in non-ciliated cells. Mechanistically, enhanced necroptosis induced by loss of cilia could be explained by induction of Ripk3 and increased abundance of autophagy components, including p62 and LC3 associated with the Ripk1/Ripk3 necrosome. Genetic ablation of cilia in renal tubular epithelial cells in mice resulted in TUNEL positivity and increased expression of Ripk3 in kidney tissue. Moreover, loss of Nphp1, the most frequent cause of NPH, further increased susceptibility to necroptosis in non-ciliated epithelial cells, suggesting that necroptosis might contribute to the pathogenesis of the disease. Together, these data provide a link between cilia-related signaling and cell death responses and shed new light on the disease pathogenesis of NPH-related ciliopathies.

Dataset Information

Primary cilia modulate TLR4-mediated inflammatory responses in hippocampal neurons.

Background

Methods

Results

Conclusions

Publications

Primary cilia modulate TLR4-mediated inflammatory responses in hippocampal neurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets