Regulation of Fibrosis by the Immune System
Introduction
Inflammation and fibrosis are two inter‐related processes with many overlapping mechanisms. An inflammatory stimulus is often necessary to initiate wound closure, where cytokines released from resident and infiltrating leukocytes stimulate proliferation and activation of myofibroblasts. However, in many cases this drive stimulates an inappropriate pro‐fibrotic response. In addition, activated myofibroblasts can take on the role of traditional APCs, secrete pro‐inflammatory cytokines, and recruit inflammatory cells to fibrotic foci, amplifying the fibrotic response in a vicious cycle. Furthermore, some myofibroblasts appear to be of bone marrow origin, and can differentiate directly from circulating monocytes (i.e., fibrocytes). Moreover, inflammatory cells have been shown to play contradictory roles in initiation, amplification, and resolution of fibrotic disease processes. The central role of the macrophage in contributing to the fibrotic response and fibrotic resolution is only beginning to be fully appreciated. Therefore, the lines between the hematopoetic/immune system and the wound healing/fibrotic system are continually blurring. Given this, it is perhaps not surprising that broadly immunosuppressive drugs that may impact both pro‐ and anti‐fibrotic aspects of the immune system have been relatively ineffective in controlling fibrotic disease progression. However, there is hope that with a better understanding of the precise cellular and biochemical processes that inter‐relate inflammatory and fibrotic disease, more specific and effective therapies can be derived.
In the following review we will first attempt to convey an understanding of the general processes involved in fibrotic disease initiation, progression, and resolution. Activation of the myofibroblast is critical for most (if not all) aspects of the fibrotic process. Second, we will discuss how the innate immune system contributes to and perhaps regulates these processes. Third, we will describe how the adaptive immune system can direct the innate response down pathways of resolution or fibrosis through production of TH1 or TH2 cytokines, respectively. Finally, we will look at therapeutic modalities in development and attempt to suggest potential new areas to explore based upon our current understanding of the inter‐relatedness of the inflammatory and fibrotic responses.
Section snippets
Fibrotic Disease Pathogenesis
Fibrosis is a leading cause of morbidity and mortality and a key component of multiple diseases affecting millions of people worldwide including: liver cirrhosis; idiopathic pulmonary fibrosis; scleroderma; diabetic retinopathy and age‐related macular degeneration; diabetic nephropathy; glomerulosclerosis and IgA nephropathy; and congestive heart failure. There are currently no approved treatments that directly target the process of fibrosis despite this large unmet medical need.
Fibrosis can
The Origin and Role of the Myofibroblast in Fibrosis
Myofibroblasts are generally believed to be the principal cell responsible for pathogenic deposition of extracellular matrix proteins within fibrotic tissue and the contraction of collagen matrix contributing to increased vascular pressure in the tissue and its associated morbidity in fibrotic disease. The ‘myofibroblast’ phenotype was first described by Gabbiani and coworkers in 1971 (Gabbiani et al., 1971) as fibroblastic cells located within granulation tissue which exhibited cytoplasmic
Inflammatory Chemokines that Regulate Fibrosis
Chemokines are potent chemoattractant peptides that may play important roles in the fibrogenic process by recruiting leukocytes and myofibroblasts to the site of injury. Several chemokines and their receptors have been shown to have critical roles in the development of fibrosis in specific animal models. In general, blockade of the TH2‐associated CC chemokines is protective from fibrosis, whereas blockade of the TH1‐associated CXC chemokines exacerbates fibrotic disease. However, there are also
The Role of Integrins in Regulating the Fibrotic Response
Integrins are a large family of heterodimeric transmembrane proteins involved in cell–cell and cell–extracellular matrix interaction originally identified as antigens that increased expression following prolonged activation of T cells (Hemler, 1990). Each integrin molecule is composed of a single α subunit and a single β subunit. There are currently 18 identified α subunits, 8 specific β subunits, and 24 distinct integrin heterodimers, as certain α and β subunits allow for promiscuous
CTGF
Connective tissue growth factor (CTGF) is a cytokine that may act downstream of TGF‐β to regulate matrix metabolism and was first identified as a product of human umbilical vein endothelial cells that was chemotactic and mitogenic for fibroblasts (Bradham et al., 1991). CTGF is expressed by fibroblasts in the lesions but not normal adjacent tissue of patients with progressive systemic sclerosis, localized scleroderma, and keloids (Igarashi et al., 1996). CTGF mRNA is upregulated in lesions of
Conclusions
Inflammation and fibrosis are two inter‐related conditions with many overlapping mechanisms. As we have observed above, an inflammatory stimulus is often necessary to initiate wound closure; however, in many cases this drive stimulates an inappropriate pro‐fibrotic response. In addition, activated myofibroblasts can take on the role of traditional APCs, secrete pro‐inflammatory cytokines, and recruit inflammatory cells to fibrotic foci, amplifying this process. M2 macrophages, TH2 T cells, and
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Current address: Frazier Healthcare Ventures, Seattle, Washington.