ECM remodelling in IBD: innocent bystander or partner in crime? The emerging role of extracellular molecular events in sustaining intestinal inflammation

IBD, which primarily includes UC and Crohn's disease (CD), is a progressive, chronic and relapsing condition. This debilitating disease is steadily becoming a worldwide medical concern, with increasing prevalence and incidence in both industrialised and developing countries.1 While the exact aetiology of the disease remains unknown, genetic predisposition and various environmental and immunological causes have been identified as contributing factors.2 Generally, IBD is characterised by a dysregulated excessive immune response and tissue damage in the GI tract.3 ,4 This aberrant and sustained immune response is thought to be mainly facilitated by defects in the function of the intestinal epithelial barrier and in the regulation of mucosal immunity.5 Yet, tissue damage associated with IBD is commonly considered solely a downstream effect and not a contributing factor. This view has led to a concentrated focus on the development of IBD treatments that target inflammatory pathways, but all, thus far, have exhibited limited efficacy. In contrast, none of the IBD drugs released to date were designed to specifically target the tissue-destructive processes associated with the disease. When it comes to basic and clinical research of IBD-associated tissue destruction, most groups have directed their efforts to investigating cellular responses during inflammation, neglecting altogether the main component undergoing physical rupture, namely, the extracellular matrix (ECM). In a similar manner, while the regulatory role of the ECM in the progression of invasive diseases, such as cancer, is becoming acknowledged, its function in IBD is often overlooked despite the common notion that tissue destruction is imperative to disease progression. In this article, we highlight ECM remodelling as an integral part of directional pathological signalling in IBD rather than, as is often considered, a passive bystander. We argue that the ECM, in the context of IBD, is not only a static scaffold holding …