Background & Aims

The mitogen- and stress-activated kinase-1 (MSK1) is a nuclear enzyme involved in a series of adaptive responses through regulating gene transcription both inside and outside of the nervous system. Recently we reported that MSK1 is present in primary sensory neurons and is needed for the development of hypersensitivity to heat stimuli (heat hyperalgesia), but not hypersensitivity to mechanical stimuli (mechanical allodynia). Here we aimed to find how MSK1 regulates the development of inflammatory heat hyperalgesia.

Methods

In addition to using global MSK1 knock out (KO) mice, we also specifically downregulated MSK1 in primary sensory neurons by delivering short hairpin RNA (shRNA) containing MSK1, transferred using adeno-associated virus (AAV), through direct injection into sciatic nerve. Then we used Hargreaves and von Frey apparatus, to assess the development of heat and mechanical hypersensitivity, respectively, in the complete Freund’s adjuvant (CFA) model of inflammation. We also utilised formalin-fixed dorsal root ganglia (DRG) and skin tissues from MSK1 global knock-out (MSK1 KO) and wild type (WT) mice for immunohistochemistry study to ascertain the role of MSK1 downregulation. Finally, we measured the core temperature mice using infrared thermometer to find out whether MSK1 deletion affects thermoregulation in our body.

Results

Here we showed that MSK1 is pivotal for inflammatory heat hyperalgesia. Both global deletion of MSK1 and specific downregulation of MSK1 in primary sensory neurons inhibit the development of inflammatory heat, but not mechanical hypersensitivity. Furthermore, we showed that this is unlikely due to immune-mediated effect of MSK1, since we reported no difference of skin microglial expression following CFA injection in both WT and MSK1 KO mice. Finally, we reasoned that in majority, this is due to MSK1 regulation on transient receptor potential vanilloid type 1 (TRPV1). Deletion of MSK1 reduces the number of TRPV1-expressing cells and inhibits inflammation-induced TRPV1 upregulation in primary sensory neurons. Interestingly, deleting MSK1 does not impair body’s thermoregulation, previously found in mice lacking TRPV1 receptor.

Conclusions

Based on these data, we propose that MSK1 serves as a master regulator in the development of inflammatory heat hyperalgesia in primary sensory neurons and it is done via the MSK1 – TRPV1 signalling pathway.

References

Reyskens, K.M. and J.S. Arthur, Emerging Roles of the Mitogen and Stress Activated Kinases MSK1 and
MSK2. Front Cell Dev Biol, 2016. 4: p. 56.
Torres-Perez, J.V., et al., Phosphorylated Histone 3 at Serine 10 Identifies Activated Spinal Neurons and
Contributes to the Development of Tissue Injury-Associated Pain. Sci Rep, 2017. 7: p. 41221.

Presenting Author

Muhammad Rizki Febrianto

Poster Authors

Muhammad Rizki Febrianto

MD, Ph.D

Imperial College London

Lead Author

Deemah Aldossary

Imperial College London

Lead Author

Vijaya Danke

Imperial College London

Lead Author

Krisztina Deák-Pocsai

Dr

University of Debrecen

Lead Author

Istvan Nagy

Imperial College London

Lead Author

Topics

  • Mechanisms: Biological-Molecular and Cell Biology