MicroRNA 15a/16‐1 suppresses aryl hydrocarbon receptor–dependent interleukin‐22 secretion in CD4+ T cells and contributes to immune‐mediated organ injury

Zhou, Lu; Liu, Jiajing; Liu, Xiaoming; Huang, Enyu; Jiao, Yang; Qian, Jiawen; Zhang, Dan; Liu, Ronghua; Chu, Yiwei

doi:10.1002/hep.29573

Cited by 24 publications

(19 citation statements)

References 36 publications

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“…Along these lines, a second study from the same group investigating the impact of IL-23 in acute liver injury confirmed a regulatory role of AHR by fine-tuning pro-inflammatory IL-17 as well as protective IL-22 responses [36]. Furthermore, the repression of AHR-dependent IL-22 expression in CD4+ T cells by microRNA 15a/16-1 led to exacerbated liver inflammation following ConA challenge, confirming the key role of AHR in controlling inflammatory responses in acute liver injury induced by ConA [37]. Interestingly, in a recent study, AHR has also been implicated in induction and mobilization of highly immunosuppressive myeloid-derived suppressor cells (MDSCs) from the peritoneal cavity.…”

Section: Ahr In Liver Immune Homeostasismentioning

confidence: 68%

The aryl hydrocarbon receptor in liver inflammation

Carambia

Schuran

2021

Semin Immunopathol

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The aryl hydrocarbon receptor (AHR) is a ubiquitously expressed ligand-activated transcription factor with multifaceted physiological functions. In the immune system, AHR has been unequivocally identified as a key regulatory factor that can integrate environmental, dietary, or microbial signals into innate and adaptive immune responses. Correspondingly, AHR activity seems to be most important at barrier organs, such as the gut, skin, and lung. The liver is likewise prominently exposed to gut-derived dietary or microbial AHR ligands and, moreover, generates plenty of AHR ligands itself. Yet, surprisingly little is known about the role of AHR in the regulation of hepatic immune responses, which are normally biased towards tolerance, preventing harmful inflammation in response to innocuous stimuli. In this review, we summarize the current knowledge about the role of AHR in hepatic immune responses in the healthy liver as well as in inflammatory liver disease. Moreover, we discuss AHR as a potential therapeutic target in hepatic disorders, including autoimmune liver disease, liver fibrosis, and liver cancer.

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Section: Ahr In Liver Immune Homeostasismentioning

confidence: 68%

The aryl hydrocarbon receptor in liver inflammation

Carambia

Schuran

2021

Semin Immunopathol

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“…All animal studies were performed in accordance with protocols approved by the Animal Subjects Committee of Beijing Anzhen Hospital. Mice carrying floxed alleles of mir15a/mir16-1 (Mirc30tm1.1Rdf/J mice) 13,14 were gifted by Dr. Yiwei Chu (Fudan University). The mice carrying floxed alleles of mir15a/mir16-1 were backcrossed to a C57BL/6 background at least ten times.…”

Section: Studies In Mouse Modelmentioning

confidence: 99%

mir15a/mir16‐1 cluster and its novel targeting molecules negatively regulate cardiac hypertrophy

Guo

Hao

et al. 2020

Clinical & Translational Med

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mir15a/mir16-1 cluster exerts protective effects against the progression of the cardiac hypertrophy and dysfunction (left). During hypertrophic stress, increased C/EBPβ downregulates the mir15a/mir16-1 cluster, resulting in up-regulation of multiple target proteins (INSR, IGF1R, AKT3, SGK1) in cardiomyocytes, causing increased activation of insulin/IGF1 signaling, ultimately causing cardiac hypertrophy and dysfunction. The CHO-PEGA delivery system replenishes mir15a/mir16-1 in the heart, attenuating cardiac hypertrophy and heat failure (right). Meanwhile, reduced circulating mir15a/mir16-1 levels are associated with the hypertrophic degree and cardiac hypertrophy risk in patients (bottom).

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“…In this regard, a key study has shown that IL‐22 promotes the expansion of liver progenitor/stem cells in mice and in patients with hepatitis B in a STAT3‐dependent manner . Furthermore, IL‐22 protects hepatocytes from apoptosis in a miR‐15a/16‐1‐dependent manner in mice . In addition, a number of studies have shown convincingly that IL‐22 strengthens the intestinal barrier by targeting intestinal stem cells and epithelial cells and by inducing important intestinal defensins or lectins such as Reg3β .…”

Section: Discussionmentioning

confidence: 99%

IL‐22 and IL‐22‐Binding Protein Are Associated With Development of and Mortality From Acute‐on‐Chronic Liver Failure

Schwarzkopf¹,

Rüschenbaum²,

Barat³

et al. 2019

Hepatol Commun

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Interleukin‐22 (IL‐22) has context‐dependent hepatoprotective or adverse properties in vitro and in animal models. IL‐22 binding protein (IL‐22BP) is a soluble inhibitor of IL‐22 signaling. The role of IL‐22 and IL‐22BP in patients with acute‐on‐chronic liver failure (ACLF) is unclear. Beginning in August 2013, patients with liver cirrhosis with and without ACLF were prospectively enrolled and followed at predefined time points. IL‐22 and IL‐22BP concentrations were quantified and associated with clinical endpoints. The impact of IL‐22BP on hepatocellular IL‐22 signaling was assessed by functional experiments. A total of 139 patients were analyzed, including 45 (32%), 52 (37%), and 42 (30%) patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, and ACLF at baseline, respectively. Serum levels of IL‐22 and IL‐22BP were strongly associated with the presence of, or progression to, ACLF (P < 0.001), and with mortality (P < 0.01). Importantly, the mean IL‐22BP levels exceeded IL‐22 levels more than 300‐fold. Furthermore, IL‐22BP/IL‐22 ratios were lowest in patients with adverse outcomes (i.e., ACLF and death). In vitro experiments showed that IL‐22BP at these concentrations inhibits hepatocellular IL‐22 signaling, including the induction of acute‐phase proteins. The capacity of patient serum to induce signal transducer and activator of transcription 3 phosphorylation was substantially higher in the presence of low versus high IL‐22BP/IL‐22 ratios. Conclusion: Our study reveals that high IL‐22 levels and low ratios of IL‐22BP/IL‐22 are associated with ACLF and mortality of patients with cirrhosis. Excessive secretion of IL‐22BP can neutralize IL‐22 in vitro and may prevent—likely in a context‐specific manner—hepatoprotective, but also adverse effects, of IL‐22 in patients with cirrhosis.

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MicroRNA 15a/16‐1 suppresses aryl hydrocarbon receptor–dependent interleukin‐22 secretion in CD4+ T cells and contributes to immune‐mediated organ injury

Cited by 24 publications

References 36 publications

The aryl hydrocarbon receptor in liver inflammation

The aryl hydrocarbon receptor in liver inflammation

mir15a/mir16‐1 cluster and its novel targeting molecules negatively regulate cardiac hypertrophy

IL‐22 and IL‐22‐Binding Protein Are Associated With Development of and Mortality From Acute‐on‐Chronic Liver Failure

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