TWEAK is increased in ulcerative colitis and contributes to fibroblast-mediated monocyte activation via heterologous non-canonical NF-kB/STAT3 signalling

Abstract

Background and AimsInteractions between fibroblasts and monocytes have emerged as a contributing factor in IBD pathogenesis and therapy resistance, owing to the ability of both cell types to participate in tissue inflammation and repair. We have previously shown that the TNF superfamily factor TWEAK (TNFSF12) can induce a UC-like inflammatory profile in colonic fibroblasts in vitro, in turn promoting monocyte adhesion and activation. However, the mechanisms underlying fibroblast-monocyte communication and its dysregulation in colitis are incompletely understood. MethodsHere we use co-culture models, human biopsies from ulcerative colitis (UC) patients and healthy donors, and public single-cell transcriptomics to characterise the mechanisms underlying fibroblast-mediated monocyte activation. ResultsWe show that TWEAK-treated inflammatory fibroblasts induce a transcriptional programme that resembles early monocyte/macrophage intermediates in UC and is enriched for genes associated with resistance to anti-TNF (TREM1, OSM, IL1B) and susceptibility to IBD (NOD2, ATG16L1). We find that conditioned media from TWEAK-treated fibroblast causes a sustained activation of STAT3 phosphorylation in monocytes, and that inhibition of the NF-{kappa}B Inducing Kinase (NIK) impairs the ability of inflammatory fibroblasts to activate STAT3 phosphorylation in monocytes, resulting in reduced expression of inflammatory mediators. Using tissues from UC patients, we show that the expansion of CD90+/PDPN+ inflammatory fibroblasts in UC correlates with the accumulation of TWEAK+ myeloid cells in the colonic mucosa, and that these fibroblasts co-localise with infiltrating monocytes in sites of active inflammation. ConclusionTogether, our findings suggest that the TWEAK/NF-{kappa}B/STAT3 axis represents an attractive target to tune inflammatory stroma/monocyte crosstalk.