A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

Fransén-Pettersson, Nina; Duarte, Nádia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D.; Hansen, Lars Bolvig; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Bjoern; Holmberg, Dan

doi:10.1371/journal.pone.0159850

Cited by 13 publications

(26 citation statements)

References 29 publications

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“…NIF mice spontaneously developed chronic liver inflammation and fibrosis initiated by a transgenic population of NKT cells while 2,4αβNOD.Rag2 +/− littermate control mice did not 34 . To gain further insight into the mechanisms underlying this process, we followed the kinetics according to the liver phenotype in mice from 3 to 18 weeks of age.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously described a new model for liver fibrosis, the nonobese diabetic inflammation and fibrosis (NIF) mouse 33 , 34 , in which a transgenic NKT cell population induces chronic inflammation and fibrosis. Here, we demonstrate that, in this model, transgenic NKT cells drive a type 1 inflammatory response through the production of pro-inflammatory cytokines involving the activation of the NLRP3 inflammasome and promote the switch to a predominantly anti-inflammatory, reparative/profibrotic response through the production of type 2 cytokines such as IL-13.…”

Section: Introductionmentioning

confidence: 99%

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NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis

Nilsson

Hörnberg²,

Schmidt-Christensen

et al. 2020

Sci Rep

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis

Nilsson

Hörnberg²,

Schmidt-Christensen

et al. 2020

Sci Rep

Self Cite

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“…ab15160, Abcam) 58 , anti-KRT7 (IHC, 1:4000, rabbit monoclonal, cat. ab181598, Abcam) 59 , anti-LEFTY1 (IHC, 1:1000, D7E3G rabbit polyclonal, cat. 12647, Cell Signalling), anti-OLFM4 (IHC, 1:200, D1E4M rabbit monoclonal, cat.…”

Section: Methodsmentioning

confidence: 99%

Single cell RNA-seq reveals profound transcriptional similarity between Barrett’s oesophagus and oesophageal submucosal glands

et al. 2018

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Barrett’s oesophagus is a precursor of oesophageal adenocarcinoma. In this common condition, squamous epithelium in the oesophagus is replaced by columnar epithelium in response to acid reflux. Barrett’s oesophagus is highly heterogeneous and its relationships to normal tissues are unclear. Here we investigate the cellular complexity of Barrett’s oesophagus and the upper gastrointestinal tract using RNA-sequencing of single cells from multiple biopsies from six patients with Barrett’s oesophagus and two patients without oesophageal pathology. We find that cell populations in Barrett’s oesophagus, marked by LEFTY1 and OLFM4, exhibit a profound transcriptional overlap with oesophageal submucosal gland cells, but not with gastric or duodenal cells. Additionally, SPINK4 and ITLN1 mark cells that precede morphologically identifiable goblet cells in colon and Barrett’s oesophagus, potentially aiding the identification of metaplasia. Our findings reveal striking transcriptional relationships between normal tissue populations and cells in a premalignant condition, with implications for clinical practice.

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“…However, the renal pathology was ameliorated in TLR4-deficient mice, suggesting that CD1d-dependent NKT cells played a protective role in NAFLD-associated renal inflammation and fibrosis via suppressing TLR4-mediated signaling function [ 67 ]. The Rag2 −/− mice overexpressing TCR Vα3.2 and Vβ9 chains showed increased generation of type II NKT cells and spontaneously developed hepatitis and liver fibrosis, in which type II NKT cells produced sufficient Th2 cytokines and contributed to the liver fibrosis [ 68 ].…”

Section: Innate Immune Cells In the Pathogenesis Of Fibrosismentioning

confidence: 99%

The Roles of Immune Cells in the Pathogenesis of Fibrosis

Huang

Peng

Xiao

et al. 2020

IJMS

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Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.

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A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

Cited by 13 publications

References 29 publications

NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis

NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis

Single cell RNA-seq reveals profound transcriptional similarity between Barrett’s oesophagus and oesophageal submucosal glands

The Roles of Immune Cells in the Pathogenesis of Fibrosis

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