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Fibrotic disease and the TH1/TH2 paradigm

Key Points

  • The tissue-repair process involves two distinct stages: a regenerative phase, in which injured cells are replaced by cells of the same type, leaving no lasting evidence of damage; and a phase known as fibroplasia or fibrotic scarring, in which connective tissue replaces normal parenchymal tissue.

  • Despite their obvious aetiological and clinical distinctions, most fibrotic diseases share a common paradigm characterized by a persistent inflammatory stimulus and lymphocyte–monocyte interactions that generate fibrogenic cytokines, which stimulate the deposition of connective tissue.

  • However, fibrosis is not always linked with robust inflammation, indicating that the mechanisms regulating fibrogenesis are distinct. Experiments using knockout mice have shown that fibrogenesis is associated with 'anti-inflammatory' T helper 2 (TH2) CD4+ T-cell responses, whereas pro-inflammatory TH1-cell responses are inhibitory.

  • Interleukin-4 (IL-4), IL-5 and IL-13, the signature TH2 cytokines, have distinct roles in the regulation of tissue remodelling and fibrosis. However, results from various experimental models indicate that IL-13 is the master regulator.

  • Transforming growth factor-β1 (TGF-β1) has been linked with the fibrosis that occurs in several diseases. Macrophages are an important source of TGF-β1, which directly activates collagen deposition by fibroblasts.

  • IL-13-secreting CD4+ TH2 cells regulate fibrogenesis directly by stimulating collagen synthesis by fibroblasts and indirectly by promoting TGF-β1 production by macrophages. IL-13 induces the production of, and activates, TGF-β1, by upregulating the expression of matrix metalloproteinases that cleave the latency-associated peptide.

  • Chemokines are strong leukocyte chemoattractants that cooperate with pro-fibrotic cytokines by recruiting macrophages and other effector cells to sites of tissue damage. CC-chemokine ligand 3 (CCL3; also known as macrophage inflammatory protein 1α) and several related CC-chemokines have been identified as essential pro-fibrotic mediators.

  • Macrophages and fibroblasts operate as key effector cells in the pathogenesis of fibrosis. The preferential activation of arginase 1 versus nitric-oxide synthase 2 in these cells might explain the potent pro-fibrotic activity of IL-13 and the antifibrotic activity of interferon-γ.

  • An attractive antifibrotic strategy would exploit the natural suppressive mechanisms of the host, which include regulatory T cells, IL-10 and the IL-13 decoy receptor.

  • Because of its ability to activate the wound-healing response, it might be more accurate to describe the TH2-cell response as an 'adaptive tissue-healing mechanism', instead of as a simple counter-regulatory system for the TH1-cell response.

Abstract

Tissue fibrosis (scarring) is a leading cause of morbidity and mortality. Current treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, hepatic fibrosis and systemic sclerosis, target the inflammatory cascade, but they have been widely unsuccessful, largely because the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation. Several experimental models have recently been developed to dissect the molecular mechanisms of wound healing and fibrosis. It is hoped that by better understanding the immunological mechanisms that initiate, sustain and suppress the fibrotic process, we will achieve the elusive goal of targeted and effective therapeutics for fibroproliferative diseases.

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Figure 1: The pathogenesis of fibrotic disease.
Figure 2: Opposing roles for TH1 and TH2 cytokines in fibrosis.
Figure 3: IL-13 and TGF-β might function independently or cooperatively to promote collagen deposition by fibroblasts.
Figure 4: Regulatory T cells, IL-10 and IL-13Rα2 function as endogenous inhibitors of tissue fibrosis.

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Acknowledgements

I sincerely thank the many colleagues who have collaborated with our group over the past several years. I greatly appreciate the generous support of D. Donaldson, J. Sypek, M. Grusby, F. Lewis, A. Cheever, D. Dunne and A. Sher.

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Thomas A. Wynn is employed by the United States Department of Health and Human Services, which holds a patent position on the treatment of fibrosis by antagonizing interleukin-13 and the interleukin-13 receptor chains. He might benefit from its commercialization.

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DATABASES

Entrez Gene

ARG1

CCL2

CCL3

CD4

IFN-γ

IL-4

IL-4Rα

IL-5

IL-10

IL-12

IL-13

IL-13Rα1

IL-13Rα2

MMP2

MMP9

NOS2

OAT

ODC

procollagen-I

procollagen-III

SMAD3

STAT6

TGF-β

TIMP1

Infectious Disease Information

schistosomiasis

FURTHER INFORMATION

Thomas Wynn's laboratory

Glossary

BLEOMYCIN

An antineoplastic antibiotic. It is active against bacteria and fungi, but its cytotoxicity has prevented its use as an anti-infective agent. Treatment with bleomycin is associated with significant pulmonary side effects — including fibrosis — that limit its use. Bleomycin was first noted to cause pulmonary fibrosis in the initial clinical trials in which it was tested. Since that time, it has been used extensively in experimental models to dissect the mechanisms of fibrosis.

CHRONIC GRANULOMATOUS RESPONSE

Granulomas are localized inflammatory reactions that contain T cells and are a form of delayed-type hypersensitivity. They have common features involving persistent antigenic stimulation that is not easily cleared by phagocytic cells. The cellular conglomerate is shielded from the healthy tissue by extracellular matrix. Granuloma formation and the fibrotic scarring that follows can cause progressive organ damage.

T HELPER 2 (TH2) CD4+ T-CELL RESPONSE

CD4+ T cells are classified according to the cytokines that they secrete. TH2 cells secrete large amounts of interleukin-4 (IL-4), IL-5 and IL-13, which promote antibody production by B cells and collagen synthesis by fibroblasts, whereas TH1 cells secrete large amounts of interferon-γ and associated pro-inflammatory cytokines. TH1-type and TH2-type cytokines can cross-regulate each other's responses. An imbalance of TH1/TH2 responses is thought to contribute to the pathogenesis of various infections, allergic responses and autoimmune diseases.

CpG-CONTAINING OLIGODEOXYNUCLEOTIDES

DNA oligodeoxynucleotide sequences that include a cytosine–guanosine sequence and certain flanking nucleotides. They have been found to induce innate immune responses through interaction with Toll-like receptor 9.

BRONCHOALVEOLAR LAVAGE

A diagnostic procedure conducted by placing a fibre-optic scope into the lung of a patient and injecting sterile saline into the lung to flush out free material. The sterile material removed contains secretions, cells and proteins from the lower respiratory tract.

CRYPTOGENIC FIBROSING ALVEOLITIS

Together with various other chronic lung disorders, cryptogenic fibrosing alveolitis is known as interstitial lung disease (ILD). ILD affects the lung in three ways: first, the tissue is damaged in some known or unknown way; second, the walls of the air sacs become inflamed; and third, scarring (or fibrosis) begins in the interstitium (tissue between the air sacs), and the lung becomes stiff.

SCLERODERMA

A chronic autoimmune disease that causes a hardening of the skin. The skin thickens because of increased deposits of collagen. There are two types of scleroderma. Localized scleroderma affects the skin in limited areas and the musculoskeletal system. Systemic sclerosis causes more widespread skin changes and can be associated with internal organ damage to the lungs, heart and kidneys.

CD4+CD25+ REGULATORY T CELLS

(TReg cells). A specialized subset of CD4+ T cells that can suppress other T-cell responses. These cells are characterized by expression of the interleukin-2 (IL-2) receptor β-chain (also known as CD25). In some cases, suppression has been associated with the secretion of IL-10, transforming growth factor-β or both.

sIL-13Rα2–Fc

A soluble protein that consists of the extracellular domain of the interleukin-13 receptor-α2 (IL-13Rα2) fused to a Gly-Ser-Gly spacer and the sequence encoding the hinge–heavy-chain constant region 2 (CH2)–CH3 regions of human IgG1. The resulting protein is a specific inhibitor of IL-13. The inhibitor prevents IL-13 from binding its signalling receptors and has been used successfully to block progressive fibrotic disease.

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Wynn, T. Fibrotic disease and the TH1/TH2 paradigm. Nat Rev Immunol 4, 583–594 (2004). https://doi.org/10.1038/nri1412

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