Funding

K.L., B.W. and M.F.N. were supported by the SFB 1181/B02, TRR241 and IZKF. The OICE instruments were funded by the DFG project numbers 441730715, 248122450 and 52732026. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) CRC1181, FOR2438, TRR241 and IZKF.

Declaration of Interests

The authors declare no competing interests.

CRediT Authorship contributions:

Kristina Lechner, M.Sc. (Conceptualization: Lead, Investigation: Lead, Formal analysis: Lead, Project Administration: Lead, Validation: Lead, Visualization: Lead, Writing – original draft: Lead), Stefanie Mott, M.Sc. (Investigation: Supporting, Formal Analysis: Supporting), Ragheed Al-Saifi, TA (Investigation: Supporting), Lisa Knipfer, PhD (Investigation: Supporting), Stefan Wirtz, MD PhD (Resources: Supporting), Raja Atreya, MD Prof. PhD (Resources: Supporting), Michael Vieth, MD Prof. PhD (Validation: Supporting), Timo Rath, MD Prof. PhD (Resources: Supporting), Tina Fraass, PhD (Methodology: Supporting), Zoltan Winter, PhD (Methodology: Supporting), Avery August, MD Prof. PhD (Resources: Supporting), Jeremy Luban, MD Prof. PhD (Resources: Supporting), Valérie S. Zimmermann, MD Prof. PhD (Resources: Supporting), Benno Weigmann, PhD (Conceptualization: Equal, Writing – original draft: Supporting, Validation: Equal, Principal Investigator: Equal), Markus Neurath, MD Prof. PhD (Conceptualization: Equal, Writing – original draft: Equal, Validation: Equal, Co-Principal Investigator: Equal).

Acknowledgments

We thank Prof. Ellmeier for providing Itk deficient mice and Prof. Eichler for advice on protein assays. We acknowledge the Optical Imaging Centre Erlangen for help with image analysis. Furthermore, we thank Dr. Sebastian Meyer, Institute of Medical Informatics, Biometry, and Epidemiology (IMBE), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), for expert help with the statistical analyses.

What you need to know:

Background and Context: CsA suppresses inflammation in UC patients but has little effects in CD. However, the reason for this remains unknown. Here, we found a link between Itk activation and CsA function.

New Findings: We demonstrate that patients with active UC show a significantly higher expression of pItk than CD patients. In experimental models we show that CsA suppresses Itk activity to block inflammation. These findings provide a possible explanation for the effects of CsA and suggest that Itk inhibitors could be used for the resolution of inflammation in UC.

Limitations: Although the solvent for the inhibitors is well tolerated, Itk inhibitors should be dissolved in water based solutions. Experimental IBD models have limitations with regard to human disease and the concept must be validated in clinical trials.

Impact: Targeting Itk leads to resolution of chronic intestinal mucosal inflammation. This study puts Itk into the focus for drug design to battle UC.

Lay Summary:

Itk is highly activated in UC patients only and CsA suppresses Itk activity. Therapeutic modulation of the CsA target Itk might be helpful for optimized therapy in UC, as inactivation of Itk leads to resolution of intestinal mucosal inflammation.