Immunological Regulation of Intestinal Fibrosis in Inflammatory Bowel Disease

Abstract

Intestinal fibrosis is a late-stage phenotype of inflammatory bowel disease (IBD), which underlies most of the long-term complications and surgical interventions in patients, particularly those with Crohn's disease. Despite these issues, antifibrotic therapies are still scarce, mainly due to the current lack of understanding concerning the pathogenetic mechanisms that mediate fibrogenesis in patients with chronic intestinal inflammation. In the current review, we summarize recent evidence regarding the cellular and molecular factors of innate and adaptive immunity that are considered critical for the initiation and amplification of extracellular matrix deposition and stricture formation. We focus on the role of cytokines by dissecting the pro- vs antifibrotic components of the immune response, while taking into consideration their temporal association to the progressive stages of the natural history of IBD. We critically present evidence from animal models of intestinal fibrosis and analyze inflammation-fibrosis interactions that occur under such experimental scenarios. In addition, we comment on recent findings from large-scale, single-cell profiling of fibrosis-relevant populations in IBD patients. Based on such evidence, we propose future potential targets for antifibrotic therapies to treat patients with IBD.

Keywords: Crohn’s disease; cytokines; fibrosis; immunoregulation; myofibroblasts; ulcerative colitis.

Figure 1.

Immunopathogenesis of intestinal response to injury. The intestinal mucosa is continuously exposed to a variety of potential harmful factors both of external (eg, infections, drugs, environmental toxins) and internal (eg, genetic, inflammatory, autoimmune) origin. The initial injury inflicted by such triggers create a breach in mucosal integrity, which allows entry of bacterial elements in deeper intestinal layers, releases various products of damaged host cells, and activates the coagulation pathway. The end product is a strong local and systemic inflammatory response that is executed via a rich network of cellular and molecular mediators, including cytokines, chemokines, and various constituents of the innate and adaptive arms of immunity. This original inflammatory response induces the enrichment of the local environment with the central cellular effector of fibrogenesis, the activated myofibroblast. Although the origin of myofibroblasts in intestinal fibrosis is still unrevealed, there are several potential sources, such as local fibroblasts and pericytes, circulating fibrocytes, as well as input by epithelial-to-mesenchymal and endothelial-to mesenchymal transition. Once activated, myofibroblasts become potent producers of ECM, which consists of collagens, fibronectin, and several other substances that occupy the intercellular space. This is a tightly regulated dynamic process encompassing a delicate balance between ECM degrading matrix metalloproteinases and their inhibitors. The final outcome is dictated by the type of the initial trigger and the ensuing response and, most importantly, by the transient or persistent nature of myofibroblast-activating stimuli. During homeostatic conditions, repair mechanisms lead to complete tissue regeneration and reestablish the structural integrity of the intestinal wall. In contrast, the chronic persistent inflammation that takes place in IBD constantly fuels profibrotic mechanisms, leading to tissue scarring and resulting in anatomical and functional compromise of the affected areas of the GI tract. Abbreviations: DAMP, damage-associated molecular patterns; ECM, extracellular matrix; IBD, inflammatory bowel disease; MMPs, matrix metalloproteinases; PAMP, pathogen-associated molecular pattern; TIMPs, tissue inhibitors of metalloproteinases.