Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma

van Gijsel-Bonnello, M.; Darling, N. J.; McDonald, L.; Sime, M.; Clark, J.; Mezna, M.; Schuettelkopf, A.; Mackay, C.; Bower, J.; McKinnon, H.; Cohen, P.; Arthur, S.

doi:10.1101/2021.06.07.447230

bioRxiv · 10.1101/2021.06.07.447230

Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma

van Gijsel-Bonnello, M.·Darling, N. J.·McDonald, L.·Sime, M.·Clark, J.·Mezna, M.·Schuettelkopf, A.·Mackay, C.·Bower, J.·McKinnon, H.·Cohen, P.·Arthur, S.

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Abstract

Interleukin-13 (IL-13) and other Th2 cytokines are important regulators of airway hyper-responsiveness, immune cell infiltration and inflammation in allergic asthma, and are produced when immune cells, such as type 2 innate lymphoid cells (ILC2s) and mast cells, are stimulated with IL-33. Here, we report that the IL-33-dependent secretion of IL-13 from ILC2s is prevented by inhibition of the salt-inducible kinases (SIKs), as we have shown previously in mast cells (Darling NJ et al., 2021, J. Biol. Chem. doi: 10.1016/j.jbc.2021.100428). We also report that a new SIK inhibitor with improved pharmacokinetic properties suppresses the recruitment of eosinophils to the lungs and serum immunoglobulin E (IgE) levels in the Alternaria alternata-induced model of allergic asthma. Our results suggest that drugs targeting SIK isoforms may have therapeutic potential for the treatment of asthma.

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van Gijsel-Bonnello, M., Darling, N. J., McDonald, L., Sime, M., Clark, J., Mezna, M., Schuettelkopf, A., Mackay, C., Bower, J., McKinnon, H., Cohen, P., Arthur, S.. 2021-06-07. Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma. https://doi.org/10.1101/2021.06.07.447230

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