In schistosomiasis and other diseases associated with type-2 immunity, the pathology resulting from chronic infection or chronic allergen exposure is predominantly induced by the host immune response. The chronic type-2 immune response eventually triggers significant fibrosis, which is the primary cause of morbidity and mortality in many chronic infectious and inflammatory diseases. Our work is focused on elucidating the mechanisms of granulomatous inflammation, fibrosis, portal hypertension, and death following infection with S. mansoni and to devise novel strategies to slow or reverse the progression of liver fibrosis. Progress was made in the following areas: 1. The liver is remarkable in its ability to regenerate despite repeated injury. Different from many other organs that utilize stem cell populations to replace tissues, the liver relies heavily upon hepatocytes and cholangiocytes to exit quiescence and divide. Recent studies have demonstrated distinct hepatocyte subsets, which contribute to hepatocyte turnover during homeostasis and during mild chronic injury. However, during severe chronic injury, damaged hepatocytes can lose the ability to divide, and in response, a population of putative hepatobiliary progenitor cells (HPCs) expands. Although several studies have questioned the source of HPCs and whether HPCs exhibit bipotent progenitor capacity, other recent studies have demonstrated that these cells can completely repopulate the liver after injuries that induce hepatocellular senescence. These differences in behavior and potency of HPCs may be explained by differences in the etiology of liver injury; nevertheless, it has been well established that the dysregulated signaling microenvironment of the injured liver can lead to aberrant proliferation of both HPCs and existing cholangiocytes (bile duct epithelial cells), together facilitating a disorganized expansion of bile ducts and recruitment of inflammatory cells known as ductular reaction (DR). DRs are encountered in virtually every acute and chronic liver disorder in which there is organ-wide liver damage and cell loss. Proliferating ductules derived from HPCs or existing cholangiocytes may fail to drain bile contents properly, leading to local necrosis and progression toward cancers such as hepatocellular or cholangiocarcinoma. Furthermore, it has been well documented that the presence of DRs is highly correlated with the progression of hepatic fibrosis and emergence of lipid abnormalities, although the mechanisms behind these correlations are debated and not well understood. Thus, the presence of DRs is an important prognostic marker of advanced liver disease, with patients exhibiting DRs generally having poor clinical outcomes. The mechanisms that govern tissue regeneration versus pathological type 2 cytokine-driven fibrosis remain unclear. Although previous studies have implicated M2 macrophages in repair and fibrosis, other cells including hepatocytes, cholangiocytes, HPCs, and fibroblasts also express functional IL-4 and IL-13 receptors, yet their roles in the progression of liver disease, steatosis, fibrosis, DRs, and liver regeneration during chronic type 2 cytokine-driven inflammatory responses were unclear. Therefore, we generated a series of cell-specific genetically ablated mice in which IL-4 receptor alpha chain (IL-4R), an essential receptor component for both IL-4 and IL-13 signaling, was targeted for deletion in biliary cells (defined as both HPCs and existing cholangiocytes), hepatocytes, and fibroblasts to elucidate the cellular pathways instructed by IL-13 that regulate the emergence of DRs and fibrosis during schistosomiasis. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis. 2. Type 2 cytokine responses, defined by the cytokines interleukin-4 (IL-4), IL-5, IL-9, and IL-13, and type 1 responses characterized by IL-12 and IFN-gamma (IFN-g) play distinct roles in immunity, inflammation, and fibrosis, and both responses undergo significant cross-regulation or suppression by the opposing pathway. In addition to suppressing type 1-driven inflammatory responses, type 2 cytokine responses are intimately involved in the activation of allergic inflammation, anti-helminth immunity, and tissue repair. In particular, the type 2 cytokine IL-13, produced by a variety of cell types including CD4+ Th2 cells, type 2 innate lymphoid cells, eosinophils, mast cells, basophils, and NK T cells, has emerged as a key cytokine in numerous type 2-driven diseases including schistosomasis. In addition to their well-defined roles in allergic disease and immunity to gastrointestinal parasites, chronic IL-13 responses are also directly involved in the development of pathological fibrosis. Nevertheless, the mechanisms by which IL-13 blockade leads to the amelioration of fibrosis and tissue remodeling remain unclear. Some studies have suggested that IL-13 directly activates the pro-fibrotic functions of macrophages and myofibroblasts. Alternatively, because IFN-g exhibits potent anti-fibrotic activity, and type 2 cytokines antagonize IFN- effector function, compensatory increases in IFN-g expression or activity following IL-13 blockade might also contribute to the reduction in fibrosis. To investigate the potential protective role of IFN-g in the development of IL-13-dependent fibrosis, we developed novel IL-13/IFN-g double cytokine-deficient mice and examined disease progression in two pulmonary and hepatic models of type 2-driven fibrosis. As predicted, we showed that fibrosis in the lung and liver are both highly dependent on IL-13. We also observed increased IFN- production and activity in the tissues of IL-13-deficient mice, suggesting that the protective anti-fibrotic effects of IL-13 deficiency might indeed be in part due to the increased IFN- response. Surprisingly, however, we observed an even greater reduction in fibrosis in the IL-13/IFN-g double deficient mice, particularly in the livers of chronically infected mice. The increased protection observed in IL-13/IFN-g mice was associated with marked decreases in Tgfb1, Mmp12, and Timp1 mRNA in the tissues; reduced inflammation; and suppression of other pro-inflammatory mediators such as TNF-alpha. Moreover, studies conducted with neutralizing mAbs to IFN-g and IL-13 confirmed these findings. Together, these studies demonstrate that the protective anti-fibrotic activity observed in IL-13-deficient mice is completely independent from increased IFN-g activity. Instead, our findings suggest that by reducing compensatory increases in type 1-associated inflammation, simultaneous reductions in IL-13 and IFN-g signaling might confer greater protection from pathological fibrosis than IL-13 blockade alone.
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