Cellular and molecular mechanisms in immune mediated hepatic fibrosis. A study of the inflammatory syndrome and fibrosis development of the NIF mouse liver

Sammanfattning: Fibrosis is the result of dysregulated inflammation and tissue repair, and is characterized by the excessive accumulation of extra cellular matrix (ECM) proteins. It causes detrimental effects to the afflicted tissue and can subsequently lead to organ failure. Sterile liver inflammation and hepatic fibrosis are associated with many liver disorders of different etiologies. Both type 1 and type 2 inflammatory responses have been reported to contribute to the pathology, however, the mechanisms controlling the balance between them are largely unknown. A major limitation in the attempts to understand the underlying mechanisms leading to fibrosis development, and to establish efficient anti-fibrotic treatment protocols has been the restricted set of suitable animal models available. In paper I, we characterize the NIF mouse, a recently established animal model that spontaneously develops chronic inflammation and fibrosis in the liver. The inflammatory syndrome is mediated by a transgenic population of Natural Killer T (NKT) cells induced on an immunodeficient NOD genetic background and is characterized by the combined production of both TH1 and TH2 cytokines. We show that the disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can reverse the disease phenotype.In paper II, we demonstrate that the transgenic NKT cells of the NIF mouse mediate the initiation of a chronic type 1 inflammatory response in the liver, involving the activation of the NLRP3 inflammasome. A subsequent shift into a type 2 inflammatory response, driven by the production of IL-33, activation of hepatic stellate cells (HSC) and production of anti-inflammatory/pro-fibrotic cytokines by the same transgenic NKT cell population, promotes the development of hepatic fibrosis. This data illustrates how plasticity in NKT cells can drive an initial type 1 inflammatory response, as well as promote the transition into a type 2 inflammatory response.Paper III illustrates how the NIF mouse model can be used for efficacy testing of drug candidates against liver fibrosis. It is imperative to develop new and improved techniques in order to be able to further investigate the pathophysiological tissue changes caused by fibrosis, as well as allowing for the possibility to monitor the effects of disease intervention protocols. In line with this, part of this dissertation work has been focused on the development of novel imaging technology for this purpose. In paper IV, we demonstrate how the anterior chamber of the eye (ACE) imaging technique can be utilized for the longitudinal in vivo study of structural changes in transplanted tissue. The disease phenotype of the NIF mouse resembles human fibrotic conditions in several pertinent features, which offers a unique opportunity to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into development of pathological fibrosis.