Fibrocytes, Inflammation, and Fibrosis in Crohn’s Disease: Another Piece of the Puzzle

Abstract

In the gut and in other organs, tissue repair following damage results from the complex interplay of chemokines, cytokines and growth factors that recruits and activates cells into the site of injury. During the initial inflammatory phase, monocytes and neutrophils remove the damaged tissue, secreting substances that activate acquired immunity, promoting tissue repair. Fibroblast activation and recruitment (as well as angiogenesis) occur at this time, mostly in response to increasing concentrations of growth factors and proinflammatory cytokines such as IL-1, IL-6, and TNF-a [1]. Subsequently, re-epithelialization accompanied by collagen/extracellular matrix (ECM) deposition and remodeling take place until specialized cells with contractile capability such as fibroblast-derived myofibroblasts restore original tissue integrity [2]. During chronic inflammation, such as that associated with inflammatory bowel diseases (IBD), excessive accumulation of ECM might lead to tissue fibrosis. While ECM deposition in ulcerative colitis appears to be limited to the superficial layers of bowel wall, in Crohn’s disease (CD) it often involves the entire wall thickness and may produce strictures, a major morbid complication of CD, often requiring surgical intervention [3]. While anti-inflammatory therapies are commonplace, little progress has been made to develop effective therapies to prevent or reverse intestinal fibrosis in CD. Although fibrosis results primarily from the rapid proliferation of the resident (local) fibroblast population in response to inflammation [4], several other mechanisms appear to account for fibrosis during inflammation, which include fibroblast migration from the surrounding tissue layers, migration and differentiation of stellate cells, epithelialand endothelial-to-mesenchymal transition (a process by which endothelial and epithelial cells lose their typical markers and acquire a spindle shape morphology), pericyte differentiation (whereas capillary lining cells assume the morphology and functions of fibroblasts) and extraintestinal fibroblast recruitment [1]. The latter might involve migration from the bone marrow and further differentiation into the site of inflammation of either mesenchymal stem cells (typical stromal cells, fibroblast-like) or hematopoietic stem cells—also called fibrocytes. While the relevance of many of these mechanisms in fibrosis development is well established for several organs, much remains to be discovered in the process of intestinal fibrosis. This is particularly true for fibrocytes, a cell line belonging to circulating ‘‘inflammatory monocytes’’ that normally replenish tissue macrophages and dendritic cells. During inflammation, under the influence of TGF-b and upon contact with T-cells, these monocytes downregulate their hematopoietic markers—CD14, CD34 and CD45— and upregulate collagen synthesizing enzymes, becoming circulating tissue fibrocytes and myofibroblasts (reviewed in [5]). Though their involvement in fibrosis development in the skin, lung, pancreas, kidney, neoplasias and blood vessels is reasonably well documented [5], their participation in the development of intestinal fibrosis is currently poorly understood. Sazuka et al. [6], in the current issue of Digestive Diseases and Sciences, implicate fibrocytes for the first time in the development of fibrosis in CD. Their report follows D. Sorrentino (&) Division of Gastroenterology, IBD Center, Virginia TechCarilion School of Medicine, 3 Riverside Circle, Roanoke, VA 24016, USA e-mail: drsorrentino@carilionclinic.org