INCREASE IN MK2 ACTIVITY IN CROHN’S DISEASE: ROLE IN THE INFLAMMATORY ACTIVATION OF FIBROBLASTS

Mesenchymal cells known as myo-/fibroblasts (MFs) are critical immunosuppressors under gut mucosal homeostasis. Expression of immune checkpoint PD-L1 by MFs plays a key role in the control T cell inflammatory responses. In Crohn’s disease (CD), switch their activity from immunosuppressive to pro-inflammatory, where they also Inflammatory Fibroblasts. However, mechanisms responsible for these pathological changes MF unknown. Map-kinase-activated protein kinase 2 (MK2) is major regulator inflammation gut. MK2 downstream p38 signaling, it evokes sub-pathway that directly regulates production cytokines implicated CD (such TNF-α, IL-1, and IL-6). Thus, we hypothesized activation signaling during immunopathogenesis CD. Human normal tissues derived MFs, well animal models relevant CD, were used this study. signaling/activity was analyzed using RNAseq, qRT-PCR, western blot (WB), cytokine/chemokine multiplex arrays, confocal microscopy. situ analysis demonstrated an increase within inflamed compared non-inflamed healthy intestinal tissues, which confirmed WB array analysis. mucosa greatly associated with mesenchymal stromal bear “myofibroblast” phenotype (positive α-SMA expression). An observed primary cultures isolated (CD-MFs) when (N-) MFs. CD-MFs significant decrease expression CCL2 IL-6. Inhibition through MK2-specific inhibitor PF-3644022 (10 μM) reversed Remarkably, differential regulation MFs: while required basal PD-L1, downregulates expression. These data indicate unique reprogramming Use therapeutic modality chronic DSS IL-10 KO murine significantly reduce MF-linked responses vivo. Our suggest toward fibroblasts. Targeting could be desirable strategy improving efficacy current IBD approaches.