Mechanisms of fibrosis: therapeutic translation for fibrotic disease

Abstract

Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.

Figure 1

Overview of wound repair and fibrosis. Epithelial and/or endothelial damage caused by various insults triggers complex interconnected wound-healing programs to quickly restore homeostasis. The coagulation pathway, which functions to stem blood loss, is triggered first, followed by acute inflammation and activation of innate immune mediators such as resident macrophages, neutrophils and dendritic cells. Epithelial and innate immune cell–derived cytokines subsequently influence the activation of the adaptive immune response. The tissue damage can also directly activate the adaptive immune response. Inflammatory and immune mediators (cytokines, chemokines and free radicals) attempt to eliminate the inciting factor while activating the resident quiescent fibroblasts into myofibroblasts that orchestrate angiogenesis and production of ECM components. Failure to adequately contain or eliminate the inciting factors can exacerbate the inflammatory response and lead to a chronic wound-healing response, with continued tissue damage, repair and regeneration, ultimately resulting in fibrosis. TSLP, thymic stromal lymphopoietin; Ab, antibody; PMN, polymorphonuclear leukocyte; EOS, eosinophil; Baso, basophil; Mast, mast cell.

Figure 2

Innate immune cells in fibrosis. The macrophage is the prototypical innate immune cell involved in chronic inflammation and fibrosis. Macrophages are generated from blood monocytes that differentiate into macrophages as they enter tissues or, in some cases, from the local proliferation of tissue-resident macrophages. Depending on their etiology, macrophages are activated by a variety of triggers. IFN-γ and/or Toll-like receptor ligands such as lipopolysaccharide (LPS) and low molecular weight hyaluronic acid (LMWHA) lead to classical activation, which is characterized by the production of reactive oxygen and nitrogen species; IL-4, IL-13 and granulocyte-macrophage colony–stimulating factor (GM-CSF) mediate alternative activation, leading to the production of polyamines and l-proline by l-arginine catabolism. Certain triggers (such as extracellular bacteria and tissue damage) also elicit persistent or recurrent neutrophil infiltration mediated by IL-17 and other neutrophil-recruiting and/or neutrophil-activating signals that can substantially augment the microbicidal and tissue-damaging activities by free radicals. Likewise, helminth antigens and allergens mediate infiltration of eosinophils that assist in parasite killing that can result in substantial collateral damage to host tissues if not tightly confined inside fibrotic granulomata. EPO, erythropoietin; MBP, myelin basic protein; EDN, eosinophil-derived neurotoxin; AAM, alternatively activated macrophage; MMP2, metalloproteinase-2; MMP9, metalloproteinase-9; CAM, classically activated macrophage; iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species.

Figure 3

Adaptive immune pathways in fibrosis. Naive CD4⁺ T cells differentiate into various distinct functional lineages driven by cues produced by injured epithelial cells and activated antigen presenting cells (dendritic cells and macrophages). Intracellular infections trigger IL-12–driven T_H1 responses that produce IFN-γ, which activates microbicidal and cytotoxic activities that aid in pathogen clearance. Extracellular bacteria and certain fungi can lead to inflammasome activation and IL-6 production and can, in the presence of TGF-β1, drive T_H17 differentiation. IL-17 from T_H17 cells helps recruit neutrophils to clear the infection and exacerbates inflammation. Infection with extracellular, tissue-dwelling helminth parasites drives T_H2 differentiation, with IL-4, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) from innate and epithelial sources guiding the differentiation of CD4⁺ T_H2 cells. IL-13, when not competed for by the higher-affinity decoy receptor IL-13Rα2, binds its signaling receptor IL-13Rα1, leading to alternative activation of macrophages as well as epithelial apoptosis and myofibroblast activation. T_reg cells are crucial in limiting the magnitude of T_H cell responses and thereby ensure proper regulation of the wound-healing response. There is also a great deal of cross-regulation among T_H cell subsets. For example, IL-13 suppresses T_H17 differentiation, whereas IFN-γ can suppress IL-13–induced fibrosis by inducing classical macrophage activation and suppressing IL-13 and TGF-β1–induced collagen synthesis in myofibroblasts. R_x, pathways being targeted for therapy, either preclinically or in clinical trials; iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; PMN, polymorphonuclear leukocyte; MUC5AC, mucin-5AC.

Figure 4

EMT in fibrosis. In mouse models of renal and hepatic fibrosis, up to 40% of α-SMA–positive, collagen-secreting myofibroblasts have been shown to arise from the differentiation of local epithelial progenitors via EMT. Repression of the transcription factors Snail1, Snail2, Zeb1 and Zeb2 are important for the maintenance of epithelial morphology. Several factors that are upregulated in the context of inflammation, including nuclear factor-κB (NF-κB), TGF-β1, bone morphogenetic proteins (BMPs), Wnt and Notch signaling proteins, can activate the Snail-Zeb pathway, leading to mesenchymal differentiation in these cells. R_x, pathways being targeted for therapy, either preclinically or in clinical trials; HA, hyaluronic acid; FSP-1, fibroblast-specific protein-1.