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Fibrosis is the major aggressive complication of Crohn’s disease (CD), causing intestinal obstruction. No targeted therapies are currently available to revert CD-associated fibrosis. While inflammatory mechanisms in CD have been extensively investigated, understanding the pathogenesis of fibrosis is relatively limited. Mesenchymal cells are believed to be the major effectors in profibrotic processes in CD. There is a dramatic increase in α-SMA expressing subsets of mesenchymal cells, also known as myofibroblasts (MF), and this is considered to be among the main hallmarks of profibrotic changes in CD. Thus, targeting the profibrotic reprogramming/increase of α-SMA+ MFs and/or fibrosis-driving signaling could lead to the development of novel anti-fibrotic approaches in CD. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream substrate of p38 and is known to regulate pro-inflammatory cytokines. Moreover, MK2 is a regulator of downstream signaling in the profibrotic non-canonical TGF-β1/p38 pathway. However, the role of MK2 in CD-associated fibrosis and profibrotic reprogramming of MFs is not known. We hypothesize that hyperactivation of MK2 is critical to the profibrotic reprogramming of MF in CD and has potential as an anti-fibrotic therapeutic target. METHODS Human normal- and CD-derived MFs were analyzed using RNAseq, cytokine/chemokine multiplex array, FACS, and confocal microscopy. Chronic IL-10 KO colitis murine models relevant to CD were used in this study. RESULTS Increased expression of MK2 within α-SMA+ mesenchymal cells was observed in stricturing CD. Ex vivo treatment of the CD tissues with MK2 inhibitor PF-3644022 (10 μM) abrogated MK2 activity and decreased expression of fibrosis-related genes. An increase in MK2 activity within intestinal MFs was observed in vivo in IL-10KO murine colitis. Therapeutic use of the MK2 inhibitor PF-3644022 (0.2 mg/kg, daily for 10 days) in vivo significantly decreased the degree of intestinal fibrosis as measured by collagen deposition and reduced the expression of fibrosis-related genes. When compared to the WT murine-derived MFs, MK2-/- MFs showed low basal and TGF-β1 induced levels of pro-fibrotic genes expression in vitro. Using primary human MFs, we found that MK2 activity was associated with hallmark profibrotic genes in CD-MFs. Inhibition of MK2 activity with PF-3644022 reduced TGF-β1-induced overexpression of Col1α2, α-SMA, TNC, Fn1, and TGF-β1 genes. Profibrotic responses in MFs through SMAD2/3 and p38, but not MAPK signaling were mediated by MK2. CONCLUSIONS Our data provide evidence that activation of MK2 drives profibrotic reprogramming of mesenchymal cells in CD and it may be an attractive therapeutic target for the development of novel targeted strategies against CD-associated fibrosis.

ACTIVATION OF MK2 IN CROHN’S DISEASE-ASSOCIATED FIBROSIS: NEW TARGET FOR ANTI-FIBROTIC THERAPY