IL‐22 and IL‐22 binding protein (IL‐22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections

Sertorio, Mathieu; Hou, Xin; Carmo, Rodrigo Feliciano do; Dessein, Hélia; Cabantous, Stéphanie; Abdelwahed, Mohammed; Romano, Audrey; Albuquerque, Fernanda Martins de; Vasconcelos, Luydson Richardson Silva; Carmo, Theomira Mauadie Azevedo; Li, Jun; Varoquaux, A.; Arnaud, Violaine; Oliveira, Pablo Rafael Silveira; Hamdoun, Anas; He, Hongbin; Adbelmaboud, Suzan; Mergani, Adil; Zhou, Jie; Monis, Ahmed; Pereira, Leila Beltrao; Halfon, Philippe; Bourlière, Marc; Paraná, Raymundo; Reis, Mitermayer Galvão dos; Gonnelli, D.; Moura, Patrícia; Elwali, Nasr Eldin; Argiro, Laurent; Li, Yuesheng; Dessein, Alain

doi:10.1002/hep.27629

Cited by 68 publications

(71 citation statements)

References 41 publications

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“…IL-22 signaling can also be regulated by a decoy receptor encoded by the gene IL22Ra2, which encodes an IL-22 binding protein. Single-nucleotide polymorphisms in the gene appear to correlate with transcript levels, as well as liver fibrosis (31).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice

et al. 2016

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Hep؊/؊ ) and Stat3 knockout (Stat3 Hep؊/؊ ) mice were generated and subjected to intra-abdominal infection with Klebsiella pneumoniae, which results in liver injury and necrosis. We found that overexpression of IL-22 or therapeutic administration of recombinant IL-22 (rIL-22), given 2 h postinfection, significantly reduced the bacterial burden in both the liver and spleen. The antimicrobial activity of rIL-22 required hepatic Il22Ra1 and Stat3. Serum from rIL-22-treated mice showed potent bacteriostatic activity against K. pneumoniae, which was dependent on lipocalin 2 (LCN2). However, in vivo, rIL-22-induced antimicrobial activity was only partially reduced in LCN2-deficient mice. We found that rIL-22 also induced serum amyloid A2 (SAA2) and that SAA2 had anti-K. pneumoniae bactericidal activity in vitro. These results demonstrate that IL-22, through IL-22Ra1 and STAT3 singling, can induce intrinsic antimicrobial activity in the liver, which is due in part to LCN2 and SAA2. Therefore, IL-22 may be a useful adjunct in treating hepatic and intra-abdominal infections.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice

et al. 2016

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“…Interestingly, the antifibrotic effect of IL-22 was associated with a significant induction of HSC senescence that expresses both the IL-22 receptors, that is, IL-10R2 and IL-22R1 [62] . Recent clinical data from patients with chronic liver infections underpin the assumption that IL-22 protects against and its competitor IL-22 binding protein (IL-22BP) aggravates liver fibrosis and cirrhosis, suggesting that the pharmacological modulation of the IL-22/IL-22BP axis may be a promising strategy to limit cirrhosis [63] . The binding of IL-22 to its decoy receptors forms a masked cytokine ( fig.…”

Section: Targeting Inflammatory Mediatorsmentioning

confidence: 99%

Liver Fibrosis: From Pathogenesis to Novel Therapies

Weiskirchen

Tacke²

2016

Dig Dis

135

100

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Chronic liver injury is accompanied by a dysbalanced scarring process, termed fibrosis. This process is mainly driven by chronic inflammation and an altered activity of a multitude of different chemokines and cytokines, resulting in the infiltration by immune cells (especially macrophages) and increase of matrix-expressing cell types. These processes might lead to cirrhosis representing the end-stage of fibrosis. Recent clinical studies comprising patients successfully treated for viral hepatitis showed that liver fibrogenesis and even cirrhosis may be reverted. The hepatic capacity to remodel scar tissue and to revert into a normal liver follows specific mechanistic principles that include the termination of chronic tissue damage, shifting the cellular bias from inflammation to resolution, initiation of myofibroblast apoptosis or senescence and, finally, fibrinolysis of excess scar tissue. The plurality of molecular and cellular triggers involved in initiation, progression and resolution of hepatic fibrogenesis offers an infinite number of therapeutic possibilities. For instance, inflammatory macrophages can be targeted via inhibition of chemokine CCL2 or its receptor CCR2 (e.g., by cenicriviroc) as well as by transfer of restorative macrophage subsets. Another target is galectin-3 that acts at various stages along the continuum from acute to chronic inflammation. Profibrogenic cytokines (e.g., transforming growth factor-β), matricellular proteins (e.g., CCN1/CYR61) or signaling pathways involved in fibrogenesis offer further possible targets. Other options are the application of therapeutic antibodies directed against components involved in biogenesis or remodeling of connective tissue such as lysyl oxidase-like-2 or synthetic bile acids like obeticholic acid that activate the farnesoid X receptor and was antifibrotic in a phase 2 study (FLINT trial). Factors affecting the gut barrier function or the intestinal microbiome further expanded the repertoire of drug targets. In this review, we discuss novel concepts in resolution of hepatic fibrosis and focus on drug targets that might be suitable to trigger resolution of fibrosis.

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“…1 Despite a significant reduction in serum ferritin, no improvement in steatosis, disease markers, or insulin resistance was noted in the treatment group. The researchers suggest that benefits observed in previous smaller, nonrandomized trials were influenced by bias.…”

Section: Does the Death Knell Toll For Phlebotomy In Nafld?mentioning

confidence: 87%

“…In this study, 1 we have excluded the possibility that the causal mutations lie outside IL22RA2. We also show that the alleles associated with a higher risk of severe fibrosis result in lower levels of IL22RA2 transcription.…”

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confidence: 99%