Elsevier

Clinics in Liver Disease

Volume 12, Issue 4, November 2008, Pages 861-882
Clinics in Liver Disease

Immune Interactions in Hepatic Fibrosis

https://doi.org/10.1016/j.cld.2008.07.002Get rights and content

Liver cirrhosis is caused by iterative cycles of tissue injury, inflammation, and repair. Although most causes of acute hepatitis resolve without scarring, chronic hepatitis is associated with persistent inflammation and matrix remodeling, which leads to fibrosis and, eventually, cirrhosis. The mechanisms that govern wound healing involve interactions between the innate and adaptive immune systems and stromal cells within a microenvironment composed of cytokines, growth factors, and modified matricellular proteins. The immune system plays a central role in the regulation of fibrosis, tissue repair, and recovery that is vital for the maintenance of tissue homeostasis. Chronic inflammation and fibrosis are inextricably linked and the cellular interactions between immune effector cells, local fibroblasts, and tissue macrophages at sites of scar formation determine the outcome of liver injury and the development of scarring.

Section snippets

Stromal microenvironments in chronic inflammatory disease

A characteristic feature of chronic liver disease is the presence of a persistent inflammatory infiltrate associated with regions of fibrosis and matrix remodeling. Although macrophages play an important role in the initiation and resolution of fibrosis, fibroblasts are the most numerous cells within the liver stroma and are primarily responsible for the synthesis of the extracellular matrix (ECM).6 Fibroblasts provide an architectural framework for tissues, and regulate important homeostatic

Macrophages regulate the induction and resolution of liver fibrosis

Many of the cells that play an important role in the immediate innate immune response, including neutrophils and mast cells, make little contribution to tissue fibrosis, and natural killer (NK) cells actually suppress fibrosis by killing activated myofibroblasts, possibly by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–dependent mechanisms,23, 24, 25 which may explain why many acute inflammatory reactions in the liver resolve without scarring.26, 27 On the other hand,

Stromal cells modulate the differentiation and function of antigen-presenting cells

The noninflamed liver contains a subset of myeloid DC that preferentially secrete IL-10 and induce IL-10 secretion in responding T cells.43, 44 These DC may play an important role in suppressing damaging immune responses in noninflammatory states. In the normal human liver, most DC are CD16+ and express high levels of CX3CL1. CD16+ circulating monocytes can differentiate into DC during the process of transendothelial migration45 and this process may be enhanced by interactions with fibroblasts.

Hepatic stellate cell activation in the liver promotes chronic inflammation

Liver myofibroblasts contribute to leukocyte recruitment to the injured liver by secreting cytokines, chemokines, and other chemoattractants, such as platelet-activating factor and complement proteins.54, 55, 56 In most circumstances, inflammation resolves once the initiating stimulus has been removed, but in some conditions, inflammation persists, resulting in chronic hepatitis and fibrogenesis.57 The switch from acute resolving to chronic persistent hepatitis is associated with the

Hepatic stellate cell activation is associated with leukocyte recruitment

Quiescent HSC are specialized pericytes found immediately adjacent to the sinusoids in the space of Disse. They maintain endothelial integrity by secreting angiogenic peptides in response to bidirectional interactions with the overlying endothelium.73 The expression of markers associated with stem cells such as CD133, Thy-1 (CD90), nanog, and Oct-4, and their ability to transdifferentiate into hepatocytes and endothelial-like cells suggest that HSC should also be regarded as progenitor cells.73

Migration and positioning of T cells are determined by patterns of cytokine and chemokine secretion within the stroma

The liver responds to injury by recruiting leukocytes from the circulation, expanding populations of scar-forming fibroblasts, and positioning the inflammatory infiltrate within the modified neomatrix. An effective hepatic immune response requires that leukocytes be recruited to the liver and then appropriately positioned at sites of injury.57 Leukocyte adhesion to endothelial cells is a prerequisite for recruitment into tissue and is regulated by a sequence of interactions in which the

Activated hepatic stellate cells modulate recruitment and positioning of leukocytes within the liver

As a consequence of being situated between the endothelium and parenchyma, HSC can participate in the recruitment of leukocytes into the liver. The first evidence that activated liver myofibroblasts contributed to liver inflammation came from the observation that CCL2 in HSC-conditioned media promoted vigorous monocyte chemotaxis.54 CCL2 also recruits memory T cells, basophils, and DC, suggesting it may be an important recruitment signal involved in chronic inflammation.102, 103 Studies in rat

Direct interactions with activated liver fibroblasts retain lymphocytes in tissue and prevent resolution of inflammation

The close temporal and spatial association between infiltrating lymphocytes and fibrosis has been recognized for many years, but the cellular interactions are poorly understood. In other tissues, T cells and B cells rely on cellular elements within the stroma for structural anchorage and directed migration. Thus, within secondary lymph nodes, fibroblastic reticular cells provide the adhesive scaffold that facilitates lymphocyte migration within the lymph node and that maintains the zonal

Stromal interactions with infiltrating lymphocytes shape fibrogenesis in chronic hepatitis

Although interactions among macrophages and fibroblasts are critical for fibrosis induction and resolution,129 the role of the adaptive immune system is less well defined (Fig. 4). Nevertheless, good evidence suggests that T cells and B cells are implicated in sustaining fibrotic responses in chronic liver disease.130 In animal models and diseased human liver, lymphocytes are seen in close association with fibroblasts in inflamed portal tracts and fibrous septa, suggesting the involvement of

Summary

Advances in our understanding of liver fibrosis have highlighted the importance of interactions between liver fibroblasts and the innate and adaptive arms of the immune system in determining the outcome following tissue injury. Although many acute injuries to the liver result in self-limiting nonfibrotic inflammatory reactions, chronic hepatitis is associated with persistent inflammation and scarring because the development of a stromal microenvironment comprising modified neomatrix, activated

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    Dr. Holt is supported by grants from the Medical Research Council, British Liver Trust, and Core.

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