Production of Profibrotic Cytokines by Invariant NKT Cells Characterizes Cirrhosis Progression in Chronic Viral Hepatitis

Abstract

Invariant (inv)NKT cells are a subset of autoreactive lymphocytes that recognize endogenous lipid ligands presented by CD1d, and are suspected to regulate the host response to cell stress and tissue damage via the prompt production of cytokines. We investigated invNKT cell response during the progression of chronic viral hepatitis caused by hepatitis B or C virus infection, a major human disease characterized by a diffused hepatic necroinflammation with scarring fibrotic reaction, which can progress toward cirrhosis and cancer. Ex vivo frequency and cytokine production were determined in circulating and intrahepatic invNKT cells from controls (healthy subjects or patients with nonviral benign or malignant focal liver damage and minimal inflammatory response) or chronic viral hepatitis patients without cirrhosis, with cirrhosis, or with cirrhosis and hepatocellular carcinoma. invNKT cells increase in chronically infected livers and undergo a substantial modification in their effector functions, consisting in the production of the type 2 profibrotic IL-4 and IL-13 cytokines, which characterizes the progression of hepatic fibrosis to cirrhosis. CD1d, nearly undetectable in noncirrhotic and control livers, is strongly expressed by APCs in cirrhotic ones. Furthermore, in vitro CD1d-dependent activation of invNKT cells from healthy donors elicits IL-4 and IL-13. Together, these findings show that invNKT cells respond to the progressive liver damage caused by chronic hepatitis virus infection, and suggest that these cells, possibly triggered by the recognition of CD1d associated with viral- or stress-induced lipid ligands, contribute to the pathogenesis of cirrhosis by expressing a set of cytokines involved in the progression of fibrosis.

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

“…Experimental studies using Con A or a-GalCer demonstrated that NKT cell activation contributes to acute hepatitis (15,16,38), likely by releasing various proinflammatory cytokines and via Fas-mediated cell lysis (4). In HBVtransgenic mice, NKT cell activation promoted fibrosis progres- sion by secreting HSC-activating cytokines IL-4 and IL-13 (39), similar to observations from patients with chronic hepatitis B (40) and consistent with the cytokine expression pattern we identified in hepatic NKT cells isolated from murine injury models in WT, but not Cxcr6 2/2 mice. In addition, Cd1d 2/2 mice lacking NKT cells were protected in thioacetamide-induced liver fibrosis (18) and in nonalcoholic steatohepatitis (19).…”

Expression of CD1d Molecules by Human Schwann Cells and Potential Interactions with Immunoregulatory Invariant NK T Cells

“…The migration and accumulation of iNKT cells toward inflammatory stimuli is well documented in various inflammatory diseases such as chronic viral hepatitis, bronchial asthma, leprosy lesions, periodontal disease tissue as well as chronic inflammatory peripheral neuropathy (38,(53)(54)(55), and is thought to be mediated through their constitutive expression of various chemokine receptors (56 -59). It has been shown in mouse models that the initial recruitment of iNKT cells does not require the presence of CD1d proteins on cells within a focus of inflammation (60).…”

Cellular and molecular mechanisms in liver fibrogenesis

“…The overall feeling is that NKT cells can promote liver fibrogenesis in HCV patients [137] as possibly also in NASH patients [138]. However, in patients affected by ALD the scenario is opposite, with chronic consumption ethanol reported to suppress activation of NKT cells, then facilitating fibrogenesis and then fibrosis.…”