Abstract
BACKGROUND: IBD is a group of diseases that have no cure and are always progressive, thus the discovery and development of new therapies is an active field of research. Biological agents have stood as a great breakthrough for improvement of patients' life quality, but only 10-30% respond to biologics and around 50% or initial responders acquire resistance over time. MAP kinase p38/MK2 pathway has been on the spot as targetable option for IBD treatment, as a master regulator of pro-inflammatory cytokines. Particularly MK2 inhibitors for clinical use are in process of development, as p38 inhibition led to unacceptable side effects when tested clinically. METHODS: Inflammation associated intestinal damage was induced in MK2 whole body KO, tissue-specific KO or each corresponding MK2 wt controls by administration of 2.5% DSS in the drinking water for 5 days, and then were allowed to recover in fresh water for an additional 4 days. Samples for pathology, protein and quantitative immunophenotyping were collected at several time points during this treatment. RESULTS: Using this mouse model of intestinal injury and inflammation, we have shown that MK2 activity is indeed required for intestinal recovery after damage; in particular, MK2 is required for neutrophil recruitment after initial damage and B and T regulatory cell recruitment in the recovery phase. Using a series of tissue-specific KO of MK2 we could identify MK2 activity in the myeloid compartment as key for restoring intestinal homeostasis after damage. CONCLUSION(S): MK2 activity is required to restore intestinal homeostasis after inflammation-induced damage.
Published Version
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