Tuning the cellular response to cytokine
The response of cells and tissues to cytokines underpins a plethora of physiology, and alterations to these responses are relevant to the pathogenesis of many diseases. Responses are ‘tuned’ in terms of magnitude, timing and molecular nature (what behaviours are stimulated or inhibited) by the encoding of cellular signalling, downstream to the reception of cytokines by cell surface receptors.
Cells use both compartmentalisation and dynamics of signalling to enable a wide range of message and thus encode complexity to signal transduction. For example, different amplitude and frequency of calcium transients results in different cell behaviours. In the context of the response to an external ligand, such as a cytokine, this allows for differential responses to similar stimuli, depending on the context, and using only a limited signalling toolkit. Many thousands of genes are induced by cytokines acting through perhaps tens of signalling cascades, some of which hinge on signaller biochemical events, bottlenecks for regulatory control.
We are investigating one such compartment of cells, and its associated machinery, which was largely ignored for over a century but has very recently become the subject of fervent biological and now biomedical research. The primary cilium is a unique, singular, nanoscale organelle assembled by the vast majority of cell types. The cilium’s associated, specialised, ‘ciliome’ is established to modulate the responses of cells to a vast array of biological, and physicochemical stimuli, most famously the response to hedgehog ligand 1. We have identified this includes potentially tuning the response of cells to inflammatory cytokines 2,3 potentially acting in concert with the ciliary compartment as a physical bottleneck for regulation of cytokine- induced signalling.
Upon exposure to cytokines we identified the cilium’s structure, trafficking within the compartment and ultimately ciliary function is altered. Moreover, this appears to be reflective of a recruitment of at least some components of the ciliome in the signalling response to cytokines, as we find genetic perturbation of these components markedly changes this response. We believe this to be by altering the dynamics of specifically NFkB signalling, potentially unveiling a unique regulatory mechanism for encoding NFkB and cytokine responses, potentially defining the downstream transcriptional signature.
Moving forward this project has a number of questions.
- What is the molecular and spatial nature of the ciliome-NFkB interface?
- Can this be targeted and exploited to tune cytokine responses?
- What is the disease relevance of these findings?
- Can the ciliome be exploited in inflammatory disease?
These questions fit alongside others in the group that all seek to understand the roles and exploitability of the ciliome in adult tissues and disease pathogenesis.
Our group is employing techniques from molecular through cell and tissue and up to pre-clinical models of disease.
This project would require genetic manipulations including RNAi, CRISPR, and CreER systems. An array of nucleic acid and protein techniques will be coupled with molecular biology and high-super resolution real-time microscopy including TIRF. In vivo research including use of both inducible cre and double transgenic labelled mice models coupled with the implementation of pre-clinical and experimental models of cytokine-driven inflammatory disease including joint, vascular and neuronal inflammation through collaborations within the Kennedy and beyond.
Bangs F, Anderson KV. Primary Cilia and Mammalian Hedgehog Signaling. Cold Spring Harb Perspect Biol. 2017 May 1;9(5). pii: a028175. doi: 10.1101/cshperspect.a028175. Review
Wann AK, Chapple JP, Knight MM. The primary cilium influences interleukin-1β-induced NFκB signalling by regulating IKK activity. Cell Signal. 2014 Aug;26(8):1735-42. doi: 10.1016/j.cellsig.2014.04.004.
Wann AK, Knight MM. Primary cilia elongation in response to interleukin-1 mediates the inflammatory response. Cell Mol Life Sci. 2012 Sep;69(17):2967-77. doi: 10.1007/s00018-012-0980-y
Maxence V. Nachury How do cilia organize signalling cascades? Philos Trans R Soc Lond B Biol Sci. 2014 Sep 5; 369(1650): 20130465. doi: 10.1098/rstb.2013.0465