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