van Gijsel-Bonnello, M. | Search bioRxiv

bioRxiv2021

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

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.

immunology↗

bioRxiv2020

IL-23 production is regulated via an MSK1/2 - CREB dependent signaling pathway downstream of Toll like receptors.

IL-23 is an IL-12 family cytokine that is important in promoting Th17 responses and has been strongly linked to autoimmunity and psoriasis. It is a heterodimeric cytokine made up of a p19 subunit unique to IL-23 and a p40 subunit that is shared with IL-12. We show here that in response to LPS, the induction of IL-23p19 mRNA is regulated by a MSK1/2 - CREB dependent pathway downstream of ERK1/2 and p38 MAPK. Knockout of MSK1/2 resulted in a decrease in both IL-23p19 mRNA transcription and IL-23 secretion in GM-CSF differentiated bone marrow cells. Similar effects were seen when the MSK1/2 phosphorylation site in CREB was mutated to alanine. Stimulation with PGE2 promotes the nuclear localisation of CRTC3, a co-activator for CREB. In combination with LPS, PGE2 promoted IL-23p19 mRNA transcription and this was blocked by knockdown of CRTC3. Imiquimod induced skin inflammation in mice has been used as a model for psoriasis and is dependent on IL-23. While MSK1/2 knockout reduced the induction of IL-23 in vivo following i.p. injection of LPS, the knockout mice were not protected from Imiquimod induced skin inflammation. MSK1/2 knockout did not reduce the induction of IL-17 producing {gamma}{delta}T cells following Imiquimod treatment, although MSK1/2 knockout did reduce the levels of these cells in mice receiving a control cream. The lack of protection in the Imiquimod model may be due to the known anti-inflammatory roles or MSKs, such as its contribution to the induction of IL-10.

immunology↗