Fibrocytes: emerging effector cells in chronic inflammation

Abstract

Fibrocytes are mesenchymal cells that arise from monocyte precursors. They are present in injured organs and have both the inflammatory features of macrophages and the tissue remodelling properties of fibroblasts. Chronic inflammatory stimuli mediate the differentiation, trafficking and accumulation of these cells in fibrosing conditions associated with autoimmunity, cardiovascular disease and asthma. This Opinion article discusses the immunological mediators controlling fibrocyte differentiation and recruitment, describes the association of fibrocytes with chronic inflammatory diseases and compares the potential roles of fibrocytes in these disorders with those of macrophages and fibroblasts. It is hoped that this information prompts new opportunities for the study of these unique cells.

Figure 1. Tissue injury, repair and remodelling

a | Current models suggest that in response to injurious stimuli, classically activated macrophages infiltrate diseased organs and mediate a programme of acute inflammation. As injury ceases and repair begins, the macrophage phenotype shifts towards that of alternative activation to dampen inflammation and promote repair. These macrophages stimulate resident fibroblasts to adopt an activated effector state characterized by the expression of α-smooth muscle actin (αSMA) and enhanced extracellular matrix (ECM) production. In the setting of severe or persistent injury, or a profibrotic milieu, this response shifts towards excessive remodelling and fibrosis. b | This model of many cells acting together is contradicted by the finding that fibrocytes have properties of both macrophages and fibroblasts. Thus, an alternative model of repair is proposed in which fibrocytes traffic to injured organs, where they participate in the inflammatory events that are also attributed to macrophages. As damage subsides, fibrocytes respond to local cues to downregulate their inflammatory responses and adopt a fibroblastic phenotype to promote repair and, in some pathological conditions, remodelling and fibrosis.

Figure 2. Characteristics of fibrocytes in tissues and in the circulation

a | A representative electron micrograph of a CD34⁺ fibrocyte in the dermis of a patient with nephrogenic sclerosing fibrosis. The presence of a large nucleus, collagen fibres and extensive processes are indicated by the arrows. In three dimensions, this cell is spindle shaped. Image is reproduced, with permission, from REF. © (2001) Lippincott Williams & Wilkins. b | A brightfield image of a fibrocyte obtained from the circulation of a normal human. c,d,e | Confocal images of this fibrocyte following staining for CD45 (bright red), intracellular pro-collagen I (green) and CD34 (dark red).

Figure 3. Differentiation pathways of macrophages, fibrocytes and fibroblasts

Fibrocytes and macrophages originate from a bone marrow-derived CD14⁺ precursor found within the circulating monocyte pool. The differentiation of macrophages is stimulated by granulocyte–macrophage colony-stimulating factor (GM-CSF), Toll-like receptor (TLR) activation and phagocytosis, T helper 1 (T_H1) cell cytokines and transendothelial migration from the blood to tissues. By contrast, the monocyte to fibrocyte transition is augmented by exposure to T_H2 cell cytokines, transforming growth factor-β1 (TGFβ1), semaphorin 7A and apoptotic cells. Further stimulation with TGFβ1 and/or endothelin 1 (ET1) can induce fibrocytes to express α-smooth muscle actin and transition to fibroblast-like effector cells. Importantly, fibroblasts are classically considered to arise from organ-specific post-embryonic mesenchymal cells, although under certain pathological conditions there might be a small contribution by epithelial cells, endothelial cells and/or circulating progenitor cells (such as mesenchymal stem cells (MSCs) and fibrocytes). Fibroblasts have remarkable phenotypical plasticity in their ability to be reprogrammed into haematopoetic stem cells and redifferentiated down the myeloid pathway in vitro, under the control of OCT4 and haematopoietic growth factors. So far, bidirectional differentiation between mature macrophages and fibroblasts has not been shown in vivo. Thus, it is most likely that, rather than acting as an intermediate population between fibroblasts and macrophages, fibrocytes are a unique cell type with properties of both macrophages and fibroblasts.

Figure 4. Potential roles of fibrocytes in chronic inflammatory disease

Using autoimmunity as a model, the possible roles of fibrocytes are proposed. In the setting of autoantigen exposure or acute injury, or following stimulation by interleukin-1β (IL-1β), serum factors and innate immune stimuli, fibrocytes adopt a pro-inflammatory phenotype characterized by the secretion of interferon-γ (IFNγ), IL-6, IL-8, CC-chemokine ligand 3 (CCL3) and CCL4. Leukocyte trafficking is enhanced through expression of intercellular adhesion molecule 1 (ICAM1). Production of extracellular matrix (ECM) components is decreased and antigen-presenting capabilities are increased by the expression of CD80, CD86 and MHC class I and II molecules. Tissue destruction may be increased by expression of matrix metalloproteinases (MMPs). As the local milieu begins to favour repair and remodelling (or perhaps concurrently with ongoing injury in the right biological context), fibrocytes adopt a more reparative phenotype. In this setting, transforming growth factor-β1 (TGFβ1) stimulates fibrocyte development through non-canonical pathways mediated by semaphorin 7A (SEMA7A) and β1 integrin, although other TGFβ1-mediated signalling pathways may also be involved. SEMA7A could activate monocytes and dendritic cells (DCs) while dampening T cell responses. ECM production is also stimulated by T helper 2 (T_H2) cell cytokines (such as IL-4 and IL-13), as well as by exposure to apoptotic cells and cellular debris. Myofibroblast transformation is promoted by TGFβ1. Platelet-derived growth factor-α (PDGFα), IL-10, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) support neoangiogenesis, and recruitment to sites of injury is promoted by the expression of chemokine receptors such as CXC-chemokine receptor 4 (CXCR4). αSMA, α-smooth muscle actin; CXCL, CXC-chemokine ligand; ERK, extracellular signal-regulated kinase; TLR, Toll-like receptor.