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  • Review Article
  • Published:

Liver fibrosis and repair: immune regulation of wound healing in a solid organ

Nature Reviews Immunology volume 14, pages 181–194 (2014)Cite this article

Subjects

Key Points

  • The liver provides a useful generic model of inflammation and repair, showing the complex interplay between the epithelial, inflammatory, myofibroblast and extracellular matrix (ECM) components of the mammalian wound-healing response. In almost all situations, fibrosis is preceded by inflammation and elements of both the innate and adaptive immune systems are crucial in regulating the fibrotic process.

  • Following liver injury, pro-inflammatory mediators that are generated by cellular damage and stimulated immune cells, as well as growth factors and cytokines (including platelet-derived growth factor, connective tissue growth factor, transforming growth factor-β and interleukin-13), activate mesenchymal precursor cells in tissues and induce their transdifferentiation into myofibroblasts. Myofibroblasts are master regulators of the fibrotic response as a result of their acquisition of scar-producing, proliferative, migratory, contractile, immunomodulatory and phagocytic properties.

  • Recent studies have used bone marrow transplantation techniques in reporter mice to show that, regardless of the aetiology or the duration of the injury, liver myofibroblasts are almost exclusively derived from the activation of resident mesenchymal cells. Perpetuation of myofibroblast fibrogenic activity is mediated through several positive feedback loops, involving the autocrine and paracrine effects of cytokines and growth factors, and cell–cell and cell–matrix interactions. Myofibroblasts themselves function as innate immune cells.

  • The balance of T helper 1 (TH1) cell-mediated and TH2 cell-mediated adaptive immune responses, the influence of unconventional T cell subsets and the equilibrium between different pro-inflammatory (that is, pro-fibrotic) and pro-resolution macrophage populations determine whether the outcome of tissue injury is homeostatic and self-limited or whether it results in pathogenic scarring.

  • Liver fibrosis in rodents and humans is a dynamic, bidirectional process that has an inherent capacity for recovery and remodelling. The loss of myofibroblasts from the hepatic scar and a crucial switch in macrophage phenotype to a pro-resolution cell type are important events in the regression of liver fibrosis that facilitate remodelling of the ECM.

  • A considerable number of tractable therapeutic targets have been identified in liver fibrosis, but clinical trials of anti-fibrotic therapies have so far been unsuccessful. Identification of the core pathways in fibrosis is likely to yield greater success in clinical translation.

Abstract

Fibrosis is a highly conserved and co-ordinated protective response to tissue injury. The interaction of multiple pathways, molecules and systems determines whether fibrosis is self-limiting and homeostatic, or whether it is uncontrolled and excessive. Immune cells have been identified as key players in this fibrotic cascade, with the capacity to exert either injury-inducing or repair-promoting effects. A multi-organ approach was recently suggested to identify the core and regulatory pathways in fibrosis, with the aim of integrating the wealth of information emerging from basic fibrosis research. In this Review, we focus on recent advances in liver fibrosis research as a paradigm for wound healing in solid organs and the role of the immune system in regulating and balancing this response.

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Figure 1: Natural history of chronic liver disease.
Figure 2: Cascade of signals following liver injury.
Figure 3: The duality of macrophages in liver fibrosis.
Figure 4: Hepatic stellate cell-derived myofibroblast fate in liver fibrosis.

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Acknowledgements

J.A.F. is supported by grants from The Health Foundation, UK, Medical Research Council, UK, and the Wellcome Trust, UK. J.P.I. is supported by grants from the Medical Research Council, the Wellcome Trust and Children's Liver Disease Foundation, UK. A.P. and P.R. are supported by grants from the Medical Research Council and the Wellcome Trust, respectively.

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Authors and Affiliations

  1. The University of Edinburgh/Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK

    Antonella Pellicoro, Prakash Ramachandran, John P. Iredale & Jonathan A. Fallowfield

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  1. Antonella Pellicoro
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  2. Prakash Ramachandran
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  3. John P. Iredale
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  4. Jonathan A. Fallowfield
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Corresponding author

Correspondence to Jonathan A. Fallowfield.

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Competing interests

J.A.F. carries out consultancy work for Novartis, UK, and Conatus Pharmaceuticals, UK. J.P.I. carries out consultancy work for UCB Celltech, UK, and GE Healthcare, UK. A.P. and P.R. declare no competing interests.

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Glossary

Myofibroblast

Fibroblast-like cell of mesenchymal origin.

Idiopathic pulmonary fibrosis

(IPF). An interstitial lung disease of unknown aetiology that is characterized by a progressive fibrotic response driven by abnormally activated alveolar epithelial cells.

Kupffer cells

Cells of the resident hepatic macrophage population. In the steady state, Kupffer cells are thought to self-renew and to originate from fetal (yolk sac) precursor cells. These cells reside in the liver sinusoids where they regulate local immune responses and remove bacteria, bacterial endotoxins and microbial debris that are derived from the gastrointestinal tract and transported to the liver via the portal vein.

Fibrocytes

Cells of haematopoietic origin (marked by CD45 expression) that can differentiate into tissue myofibroblasts.

Pericytes

Specialized mesenchymal cells that are embedded within the basement membrane of capillaries (hepatic stellate cells are considered to be the pericytes of the liver).

Space of Disse

The perisinusoidal space in the liver, between the endothelial cells and the hepatocytes.

Integrins

A family of transmembrane receptors composed of non-covalently linked heterodimers of α-subunits and β-subunits that form at least 24 combinations in mammalian tissues. Several integrins, in particular β3 integrins, recognize a tripeptide arginine–glycine–aspartic acid (RGD) sequence in specific ECM ligands.

Cd11b–DTR transgenic mice

Transgenic mice that express the human diphtheria toxin receptor (DTR) under the control of the Cd11b promoter, which facilitates the selective depletion of monocytes and macrophages by the administration of diphtheria toxin.

Natural killer T cells

(NKT cells). A subset of T cells that have characteristics of both T cells and NK cells, expressing both a T cell receptor and NK lineage markers.

Innate-like invariant NKT cells

(iNKT cells). A subset of natural killer T cells that express a T cell receptor (TCR) with an invariant Vα14-Jα18 TCRα chain paired with a restricted subset of TCR Vβ chains. iNKT cells exclusively recognize glycolipid antigens that are presented on CD1d molecules.

γδ T cells

A subset of T cells that are defined by the genetic composition of their T cell receptor; the TCR is made up of one γ-chain and one δ-chain, rather than the one α-chain and one β-chain that are found in classical αβ T cells.

Innate lymphoid cells

Innate immune cells that produce many T helper cell-associated cytokines but do not express cell surface markers that are associated with other immune cell lineages. In addition, these cells do not express a T cell receptor and do not respond in an antigen-specific manner.

Senescent

A cellular state in which a growth arrest programme has been initiated that limits the lifespan of the cell and prevents unlimited cell proliferation.

Glitazones

Drugs used for the treatment of type 2 diabetes mellitus that function as agonists of peroxisome proliferator-activated receptor-γ (PPARγ) and that increase insulin sensitivity.

M1 macrophage

A macrophage that is activated by interferon-γ or by lipopolysaccharide; also known as a classically activated macrophage. These cells express pro-inflammatory cytokines and inducible nitric oxide synthase (among other things), and they inhibit cell proliferation and cause tissue damage.

M2 macrophage

A macrophage that is activated by the T helper 2 cell cytokines interleukin-4 (IL-4) and IL-13; also known as an alternatively activated macrophage. These cells express arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain (among other things), and they promote cell proliferation and tissue repair.

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Pellicoro, A., Ramachandran, P., Iredale, J. et al. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 14, 181–194 (2014). https://doi.org/10.1038/nri3623

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