Abstract
Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies. Both type 1 and type 2 inflammatory responses have been reported to contribute to liver pathology. However, the mechanisms controlling the balance between these responses are largely unknown. Natural killer T (NKT) cells can be activated to rapidly secrete cytokines and chemokines associated with both type 1 and type 2 inflammatory responses. As these proteins have been reported to accumulate in different types of sterile liver inflammation, we hypothesized that these cells may play a role in this pathological process. We have found that a transgenic NKT (tgNKT) cell population produced in the immunodeficient 2,4αβNOD.Rag2−/− mice, but not in 2,4αβNOD.Rag2+/− control mice, promoted a type 1 inflammatory response with engagement of the NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome. The induction of the type 1 inflammatory response was followed by an altered cytokine profile of the tgNKT cell population with a biased production of anti-inflammatory/profibrotic cytokines and development of liver fibrosis. These findings illustrate how the plasticity of NKT cells modulates the inflammatory response, suggesting a key role for the NKT cell population in the control of sterile liver inflammation.
Highlights
Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies
Relevant animal models are essential to extend our understanding of the mechanisms underlying sterile liver inflammation and fibrosis, including NAFLD and nonalcoholic steatohepatitis (NASH), and to provide pertinent tools for preclinical drug testing
We show how the accumulation of Natural killer T (NKT) cells in the livers of nonobese diabetic inflammation and fibrosis (NIF) mice precedes the recruitment of other inflammatory cells by approximately 2 weeks, suggesting that this NKT cell population mediates the initial events in liver pathogenesis
Summary
Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies. Natural killer T (NKT) cells can be activated to rapidly secrete cytokines and chemokines associated with both type 1 and type 2 inflammatory responses As these proteins have been reported to accumulate in different types of sterile liver inflammation, we hypothesized that these cells may play a role in this pathological process. An initial phase of recruitment and activation of innate immune cells that includes the production of pro-inflammatory cytokines and chemokines, such as IL-6, TNFα and CC motif chemokine ligand 2 (CCL2), drives the type 1 inflammatory response that contributes to local tissue destruction This proinflammatory response triggers the immune system to prepare for a transition to repair mode, in which key inflammatory cells such as KCs and monocyte-derived macrophages switch from a type 1 pro-inflammatory to a type 2 anti-inflammatory/reparative r esponse[9,11]. These subsets play important roles in the regulation of liver inflammation, where they influence other inflammatory cells through their innate-like property of rapid secretion of both pro-inflammatory and anti-inflammatory cytokines. iNKT21,30,31 and type 2 NKT32 cells have been described as having both immunostimulatory and regulatory properties that enable their roles as mediators of inflammatory responses in many diseases
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