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.