Immune interactions in hepatic fibrosis

Abstract

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.

Figure 1

Based on work in other tissues the figure shows the two main monocyte subsets in blood and how they can give rise to functionally diverse subsets of kupffer cells, macrophages and myeloid DCs after recruitment into the liver. Two distinct subpopulations of monocytes can be identified in the human circulation which show differences in expression of chemokine receptors and adhesion molecules involved in recruitment through sinusoidal endothelium. Adapted from .

Figure 2. Activated hepatic stellate cells control many aspects of tissue inflammation

Following activation HSC undergo a phenotypic switch adopting a myofibroblast morphology and upregulating pro-inflammatory cytokines that regulate stromal immune responses as well as secreting fibrillar collagens and neo-matricellular proteins that generate tissue scarring. See text for further discussion.

Figure 3. Real-time lymphocyte chemotaxis to liver fibroblast conditioned media

Directed real-time migration of fluorescently labelled human lymphocytes towards liver fibroblast conditioned media. Conditioned supernatant taken from human liver fibroblasts isolated from diseased livers contains soluble factors that promote rapid lymphocyte chemotaxis even in the absence of proinflammatory cytokine stimulation. Data represents mean ± SEM 3 replicate experiments.

Figure 4

Liver fibrosis is the product of interactions between stromal cells and the innate and adaptive immune systems. For further discussion see text.