The Proteomic Signature of Tissue Remodeling in Chronic Intestinal Inflammation

Tissue remodeling and fibrosis are key problems in patients with inflammatory bowel diseases (Crohn’s disease, ulcerative colitis).1, 2, 3, 4 Many patients have to undergo surgery owing to strictures and stenoses, underlining the clinical relevance of this problem. In Crohn’s disease, population-based studies have suggested that approximately 20% of patients suffer from fibrostenosis (mainly in the terminal ileum and to a lesser extent in the colon) within 20 years of clinical diagnosis.^2,5 In contrast, 2%–11% of patients with ulcerative colitis have fibrosis-associated strictures (benign strictures or colitis-associated, cancer-induced strictures) compared with approximately 8% of patients with colonic Crohn’s disease.² However, histologic evidence of fibrosis is present in almost all colonic specimens from patients with ulcerative colitis, highlighting the relevance of tissue fibrosis in this disease.

However, what are the key regulatory proteins associated with tissue fibrosis in the chronically inflamed colon? In this issue of Cellular and Molecular Gastroenterology and Hepatology, Moutin et al⁶ address this issue by studying the proteomic signature of the chronically inflamed colon. They took advantage of the mucin 2 knockout model, a murine model of chronic intestinal inflammation associated with tissue remodeling that mimics some features of ulcerative colitis in human beings. In particular, crypt hyperplasia, mucosal immune cell infiltration, as well as preneoplastic features such as dysplasia are seen in this model, highlighting its potential relevance for inflammatory bowel diseases in human beings. The authors then used label-free, mass-spectrometry–based proteomic strategies based on comprehensive data-independent acquisition to study signatures and signaling nodes in the inflamed tissue. In particular, they studied the global composition of the extracellular matrix proteome or matrisome, which is defined as an ensemble of more than 1000 genes encoding extracellular matrix and extracellular matrix–associated proteins. Thus, the matrisome not only includes all the genes encoding structural extracellular matrix components (eg, glycoproteins, collagens, proteoglycans), but also genes encoding proteins that interact with or remodel the extracellular matrix (eg, matrix-affiliated proteins, extracellular matrix regulators, secreted factors).⁷

In an elegant series of studies, Moutin et al⁶ analyzed the matrisome before the onset of colitis and after development of a full colitis phenotype. Through these experiments they described unique proteomic profiles even before the onset of colitis, as well as in chronic intestinal inflammation. They further integrated proteomic and transcriptomic data sets to determine matrisomal proteins in mucin 2–deficient mice. Based on this approach, they could add 34 proteins to the known matrisomal signature. Importantly, they noted key differences in the expression of small leucine-rich proteoglycans in animals with chronic colitis compared with uninflamed tissue. Furthermore, they identified many differentially expressed proteins in the histologically normal mucosa in mucin 2 knockout mice, suggesting the presence of abnormal matrisome composition before the clinical onset of colitis. Moutin et al⁶ speculated that abnormal expression of small leucine-rich proteoglycans may be associated with p53 activation, thereby potentially explaining an increased risk for the development of neoplasias in this model. The findings by Moutin et al⁶ indicate interactions between matrisomal proteins and immune cells such as lymphocytes and macrophages in the inflamed colon. Moreover, proteomic signatures also suggested important interactions between matrisomal proteins and tissue resident cells, such as endothelial cells and fibroblasts, before the development of macroscopic colitis.

The work by Moutin et al⁶ makes an important contribution to our understanding of tissue remodeling in colitis. It indicates a central role of matrisomal proteins in tissue remodeling during chronic intestinal inflammation. Furthermore, the findings highlight a potential role of endothelial cells and fibroblasts early in the process of tissue remodeling. Moreover, these data indicate the existence of characteristic proteomic signatures during chronic colitis that open new avenues for research. In particular, Moutin et al⁶ identified control nodes with characteristic signaling pathways that could be studied further to define new targets for clinical therapy of inflammatory bowel diseases and the prevention of colitis-associated colon cancer. Further work should address the proteomic signatures in other models of chronic intestinal inflammation and patients with inflammatory bowel diseases and study potential translational targeting of matrisome components to further explore the clinical relevance of the observed extracellular matrix alterations.