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Andreas Diefenbach - One of the best experts on this subject based on the ideXlab platform.

  • a catch 22 Interleukin 22 and cancer
    European Journal of Immunology, 2018
    Co-Authors: Pedro P Hernandez, Konrad Gronke, Andreas Diefenbach
    Abstract:

    Barrier surfaces of multicellular organisms are in constant contact with the environment and infractions to the integrity of epithelial surfaces is likely a frequent event. Interestingly, components of the immune system, that can be activated by environmental compounds such as the microbiota or nutrients, are interspersed among epithelial cells or directly underlie the epithelium. It is now appreciated that immune cells continuously receive and integrate signals from the environment. Curiously, such continuous reception of stimulation does not normally trigger an inflammatory response but mediators produced by immune cells in response to such signals seem to rather promote barrier integrity and repair. The molecular mediators involved in this process are poorly understood. In recent years, the cytokine Interleukin-22, produced mainly by group 3 innate lymphoid cells (ILCs), has been studied as a paradigm for how immune cells can control various aspects of epithelial cell function because expression of its receptor is restricted to non-hematopoietic cells. We will summarize here the diverse roles of IL-22 for the malignant transformation of epithelial cells, for tumor growth, wound healing and tissue repair. Furthermore, we will discuss IL-22 as a potential therapeutic target.

  • control of epithelial cell function by Interleukin 22 producing rorγt innate lymphoid cells
    Immunology, 2011
    Co-Authors: Stephanie L Sanos, Arthur Mortha, Cedric Vonarbourg, Andreas Diefenbach
    Abstract:

    Summary It is rapidly emerging that the defence system of innate lymphocytes is more diverse than previously recognized. In addition to natural killer (NK) cells, lymphoid tissue inducer (LTi) cells, and natural helper cells have now been identified. LTi cells are developmentally dependent on the orphan transcription factor RORct and instruct lymph node development during embryogenesis. More recently, it has become evident, that in addition to their role for lymph organ development, LTi cells are also potent producers of cytokines such as Interleukin-22 (IL-22) and IL-17 in adult mice. In addition to LTi cells, another RORct-dependent innate lymphocyte subset co-expressing RORct and NK cell receptors (NKRs) has been identified. These NKR + RORct + cells are also potent producers of IL-22 but it is unclear whether they are part of the NK cell or LTi cell lineage. This review will highlight recent progress in understanding development and function of innate IL-22-producing lymphocyte subsets.

  • rorγt and commensal microflora are required for the differentiation of mucosal Interleukin 22 producing nkp46 cells
    Nature Immunology, 2009
    Co-Authors: Stephanie L Sanos, Andreas Diefenbach, Arthur Mortha, Karin Oberle, Charlotte Heners, Caroline Johner
    Abstract:

    Mouse lymphoid tissue–inducer (LTi) cells require the transcription factor RORγt. Cupedo's group identifies RORγt+ human LTi cell equivalents as committed natural killer cell precursors, and teams led by Vivier and Diefenbach describe RORγt-expressing Interleukin 22–producing natural killer cells in mouse gut.

  • rorγt and commensal microflora are required for the differentiation of mucosal Interleukin 22 producing nkp46 cells
    Nature Immunology, 2009
    Co-Authors: Stephanie L Sanos, Andreas Diefenbach, Arthur Mortha, Karin Oberle, Charlotte Heners, Caroline Johner, Viet L Bui
    Abstract:

    The mucosal immune system of the intestine is separated from a vast array of microbes by a single layer of epithelial cells. Cues from the commensal microflora are needed to maintain epithelial homeostasis, but the molecular and cellular identities of these cues are unclear. Here we provide evidence that signals from the commensal microflora contribute to the differentiation of a lymphocyte population coexpressing stimulatory natural killer cell receptors and the transcription factor RORgammat that produced Interleukin 22 (IL-22). The emergence of these IL-22-producing RORgammathiNKp46+NK1.1(int) cells depended on RORgammat expression, which indicated that these cells may have been derived from lymphoid tissue-inducer cells. IL-22 released by these cells promoted the production of antimicrobial molecules important in the maintenance of mucosal homeostasis.

Bin Gao - One of the best experts on this subject based on the ideXlab platform.

  • Interleukin 22 in alcoholic hepatitis and beyond
    Hepatology International, 2020
    Co-Authors: Seonghwan Hwang, Xiaogang Xiang, Dechun Feng, Vijay H Shah, Bin Gao
    Abstract:

    Alcoholic hepatitis (AH) is a clinical syndrome characterized by jaundice and progressive inflammatory liver injury in patients with a history of prolonged periods of excess alcohol consumption and recent heavy alcohol abuse. Severe AH is a life-threatening form of alcohol-associated liver disease with a high short-term mortality rate around 30–50% at one month from the initial presentation. A large number of pro-inflammatory mediators, metabolic pathways, transcriptional factors and epigenetic factors have been suggested to be associated with the development and progression of AH. Several factors may contribute to liver failure and mortality in patients with severe AH including hepatocyte death, inflammation, and impaired liver regeneration. Although the pathogeneses of AH have been extensively investigated and many therapeutic targets have been identified over the last five decades, no new drugs for AH have been successfully developed. In this review, we discuss Interleukin-22 (IL-22) biology and its roles of anti-apoptosis, anti-fibrosis, anti-oxidation, anti-bacterial infection and regenerative stimulation in protecting against liver injury in many preclinical models including several recently developed models such as chronic-plus-binge ethanol feeding, acute-on-chronic liver failure, C-X-C motif chemokine ligand 1 plus high-fat diet-induced nonalcoholic steatohepatitis. Finally, clinical trials of IL-22 for the treatment of AH are also discussed, which showed some promising benefits for AH patients.

  • Interleukin 22 ameliorates neutrophil driven nonalcoholic steatohepatitis through multiple targets
    Hepatology, 2020
    Co-Authors: Seonghwan Hwang, Xiaogang Xiang, Dechun Feng, George Kunos, Tianyi Ren, Wonhyo Seo, Seungjin Kim, Seol Hee Park, Zhou Zhou, Bin Gao
    Abstract:

    Background and aims Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C-X-C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high-fat diet (HFD)-fed mice. The aim of this study was to test whether overexpression of CXCL1 itself in the liver can induce NASH in HFD-fed mice and to test the therapeutic potential of IL-22 in this new NASH model. Approach and results Overexpression of Cxcl1 in the liver alone promotes steatosis-to-NASH progression in HFD-fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as apoptosis signal-regulating kinase 1 and p38 mitogen-activated protein kinase) activation. Myeloid cell-specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1-induced NASH and stress kinase activation in HFD-fed mice. Treatment with Interleukin (IL)-22, a cytokine with multiple targets, ameliorated CXCL1/HFD-induced NASH or methionine-choline deficient diet-induced NASH in mice. Mechanistically, IL-22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL-22 treatment attenuated the inflammatory functions of hepatocyte-derived, mitochondrial DNA-enriched extracellular vesicles, thereby suppressing liver inflammation in NASH. Conclusions Hepatic overexpression of CXCL1 is sufficient to drive steatosis-to-NASH progression in HFD-fed mice through neutrophil-derived reactive oxygen species and activation of stress kinases, which can be reversed by IL-22 treatment via the induction of metallothionein.

  • Interleukin 22 acts as a mitochondrial protector
    Theranostics, 2020
    Co-Authors: Seonghwan Hwang, Dechun Feng, Bin Gao
    Abstract:

    Interleukin (IL)-22 has been increasingly recognized as a promising therapeutic option for various types of diseases. This commentary summarizes the novel mechanistic aspects of IL-22 for the treatment of liver diseases including the study by Chen et al. published in the recent issue of the Theranostics that elucidated the novel function of IL-22 as a mitochondrial protector for the adaptive defense against liver injury.

  • Interleukin 22 prevents microbial dysbiosis and promotes intestinal barrier regeneration following acute injury
    Shock, 2017
    Co-Authors: Adam M Hammer, Bin Gao, Niya L Morris, Abigail R Cannon, Omair M Khan, Robin C Gagnon, Nellie V Movtchan, Ilse Van Langeveld, Mashkoor A Choudhry
    Abstract:

    Intestine barrier disruption and bacterial translocation can contribute to sepsis and multiple organ failure, leading causes of mortality in burn-injured patients. In addition, findings suggest that ethanol (alcohol) intoxication at the time of injury worsens symptoms associated with burn injury. We have previously shown that Interleukin-22 (IL-22) protects from intestinal leakiness and prevents overgrowth of gram-negative bacteria following ethanol and burn injury, but how IL-22 mediates these effects has not been established. Here, utilizing a mouse model of ethanol and burn injury, we show that the combined insult results in a significant loss of proliferating cells within small intestine crypts and increases Enterobacteriaceae copies, despite elevated levels of the antimicrobial peptide lipocalin-2. IL-22 administration restored numbers of proliferating cells within crypts, significantly increased Reg3β, Reg3γ, lipocalin-2 AMP transcript levels in intestine epithelial cells, and resulted in complete reduction of Enterobacteriaceae in the small intestine. Knockout of signal transducer and activator of transcription factor-3 (STAT3) in intestine epithelial cells resulted in complete loss of IL-22 protection, demonstrating that STAT3 is required for intestine barrier protection following ethanol combined with injury. Together, these findings suggest that IL-22/STAT3 signaling is critical to gut barrier integrity and targeting this pathway may be of beneficial clinical relevance following burn injury.

  • therapeutic role of Interleukin 22 in experimental intra abdominal klebsiella pneumoniae infection in mice
    Infection and Immunity, 2016
    Co-Authors: Mingquan Zheng, William Horne, Jeremy P Mcaleer, Derek Pociask, Taylor Eddens, Misty Good, Bin Gao, Jay K Kolls
    Abstract:

    Interleukin 22 (IL-22) is an IL-10-related cytokine produced by T helper 17 (Th17) cells and other immune cells that signals via IL-22 receptor alpha 1 (IL-22Ra1), which is expressed on epithelial tissues, as well as hepatocytes. IL-22 has been shown to have hepatoprotective effects that are mediated by signal transducer and activator of transcription 3 (STAT3) signaling. However, it is unclear whether IL-22 can directly regulate antimicrobial programs in the liver. To test this hypothesis, hepatocyte-specific IL-22Ra1 knockout (Il22Ra1(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.

Wei Chen - One of the best experts on this subject based on the ideXlab platform.

  • vegf b antibody and Interleukin 22 fusion protein ameliorates diabetic nephropathy through inhibiting lipid accumulation and inflammatory responses
    Acta Pharmaceutica Sinica B, 2021
    Co-Authors: Yilan Shen, Wei Chen, Jiajun Fan, Xin Jin, Lei Han, Qi Bian, Zhonglian Cao, Tao Ding, Zongshu Xian
    Abstract:

    Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of Interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction. Moreover, the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity. Collectively, our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN, which highlighted a novel therapeutic approach to DN.

  • Interleukin 22 mediated renal metabolic reprogramming via pfkfb3 to treat kidney injury
    bioRxiv, 2020
    Co-Authors: Wei Chen, Yilan Shen, Jiajun Fan, Xian Zeng, Xuyao Zhang, Jingyun Luan, Jinghui Zhang
    Abstract:

    Abstract Kidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end-stage renal disease (ESTD). Interleukin 22 (IL-22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here we first provide evidence that IL-22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL-22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL-22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL-22 are certificated in cisplatin induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL-22 on kidney and highlight the therapeutic opportunities of IL-22 and the involved metabolic regulators in various kidney diseases.

  • Interleukin 22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury
    Theranostics, 2020
    Co-Authors: Wei Chen, Jiajun Fan, Xian Zeng, Xuyao Zhang, Jingyun Luan, Wenjing Zai, Yichen Wang, Yilan Shen
    Abstract:

    Rationale: Interleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Methods: Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Utilizing cell biological, molecular, and biochemical approaches, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. Results: IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial dysfunction. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Conclusions: Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases.

  • Interleukin 22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury
    bioRxiv, 2020
    Co-Authors: Wei Chen, Yilan Shen, Jiajun Fan, Xuyao Zhang, Jingyun Luan, Wenjing Zai, Yichen Wang
    Abstract:

    Interleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Specifically, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases. Graphical AbstractOur works demonstrate a critical role of IL-22 in regulating hepatocellular metabolism to treat liver injury via activating STAT3-lncRNA H19-AMPK-AKT-mTOR axis. These findings describe a novel mechanism underscoring the regulation of metabolic states of hepatocytes by IL-22 during liver injury with potentially broad therapeutic insights. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/892927v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@c6308corg.highwire.dtl.DTLVardef@19d6e17org.highwire.dtl.DTLVardef@a6e661org.highwire.dtl.DTLVardef@15f129e_HPS_FORMAT_FIGEXP M_FIG C_FIG

  • targeted Interleukin 22 gene delivery in the liver by polymetformin and penetratin based hybrid nanoparticles to treat nonalcoholic fatty liver disease
    ACS Applied Materials & Interfaces, 2019
    Co-Authors: Wenjing Zai, Wei Chen, Jiajun Fan, Xuyao Zhang, Jingyun Luan, Xin Jin, Shijie Tang, Xiaobin Mei, Qiang Hao, Hongrui Liu
    Abstract:

    Nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease, and there is currently no available treatment strategy. Interleukin-22 (IL-22) has been recognized as a promising agent for alleviating NAFLD, but the efficacy of IL-22 is far from satisfactory because safe dose of IL-22 elicited limited improvement, whereas higher concentration might induce serious side effects and off-target toxicities. Thus, targeted and sustained expression of IL-22 in the liver is necessary. To meet the challenge, we elaborately developed a novel polymetformin carrier by conjugating biguanide to chitosan, termed chitosan–metformin (CM), which could exert advanced gene delivery efficiency and possess intrinsic therapeutic efficacy from metformin for NAFLD. CM accompanied with penetratin and DSPE-PEG2000 could self-assemble to form stable nanocomplexes with IL-22 gene via electrostatic interaction. This nanoparticle (CDPIA) exerted desirable particle size at ∼100 nm, fine morphology, and efficient...

Jeanchristophe Renauld - One of the best experts on this subject based on the ideXlab platform.

  • The Chemokine Receptor CXCR6 Controls the Functional Topography of Interleukin-22 Producing Intestinal Innate Lymphoid Cells
    Immunity, 2014
    Co-Authors: Naoko Satoh-takayama, Jeanchristophe Renauld, Nicolas Serafini, Thomas Verrier, Abdessalem Rekiki, Gad Frankel, James P Di Santo
    Abstract:

    SUMMARY Interleukin-22 (IL-22) plays a critical role in mucosal defense, although the molecular mechanisms that ensure IL-22 tissue distribution remain poorly under-stood. We show that the CXCL16-CXCR6 chemo-kine-chemokine receptor axis regulated group 3 innate lymphoid cell (ILC3) diversity and function. CXCL16 was constitutively expressed by CX3CR1 + intestinal dendritic cells (DCs) and coexpressed with IL-23 after Citrobacter rodentium infection. In-testinal ILC3s expressed CXCR6 and its ablation generated a selective loss of the NKp46 + ILC3 subset, a depletion of intestinal IL-22, and the inability to control C. rodentium infection. CD4 + ILC3s were unaffected by CXCR6 deficiency and remained clustered within lymphoid follicles. In contrast, the lamina propria of Cxcr6 À/À mice was devoid of ILC3s. The loss of ILC3-dependent IL-22 epithelial stimulation reduced antimicrobial peptide expression that explained the sensitivity of Cxcr6 À/À mice to C. rodentium. Our results delineate a critical CXCL16-CXCR6 crosstalk that coordinates the intes-tinal topography of IL-22 secretion required for mucosal defense.

  • activation of type 3 innate lymphoid cells and Interleukin 22 secretion in the lungs during streptococcus pneumoniae infection
    The Journal of Infectious Diseases, 2014
    Co-Authors: Laurye Van Maele, Christophe Carnoy, Delphine Cayet, Stoyan Ivanov, Remi Porte, Emeric Deruy, Jose A Chabalgoity, Jeanchristophe Renauld, Gerard Eberl
    Abstract:

    Mucosal sites are continuously exposed to pathogenic microorganisms and are therefore equipped to control respiratory infections. Type 3 innate lymphoid cells (ILC3) are key players in antimicrobial defense in intestinal mucosa, through Interleukin 17 and Interleukin 22 (IL-22) production. The present study aimed at analyzing the distribution and function of ILC3 in the respiratory tract. We first observed that lung mucosa harbors a discrete population of ILC3 expressing CD127, CD90, CCR6, and the transcriptional factor RORγt. In addition, lung ILC3 were identified as a major source of IL-22 in response to Interleukin 23 stimulation. During Streptococcus pneumoniae infection, ILC3 rapidly accumulated in the lung tissue to produce IL-22. In response to S. pneumoniae, dendritic cells and MyD88, an important adaptor of innate immunity, play critical functions in IL-22 production by ILC3. Finally, administration of the Toll-like receptor 5 agonist flagellin during S. pneumoniae challenge exacerbated IL-22 production by ILC3, a process that protects against lethal infection. In conclusion, boosting lung ILC3 might represent an interesting strategy to fight respiratory bacterial infections. © The Author 2014.

  • proinflammatory role of the th17 cytokine Interleukin 22 in collagen induced arthritis in c57bl 6 mice
    Arthritis & Rheumatism, 2009
    Co-Authors: Lies Geboes, Jeanchristophe Renauld, Laure Dumoutier, Hilde Kelchtermans, Evelien Schurgers, Tania Mitera, Patrick Matthys
    Abstract:

    Objective. To investigate the role of Interleukin-22 (IL-22) in collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. Methods. C57BL/6 mice were immunized with type II collagen (CII) in Freund's incomplete adjuvant with added Mycobacterium tuberculosis, and levels of IL-22 and its specific receptor, IL-22 receptor type I (IL-22RI), were measured in sera and tissue by enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction analysis. Clinical and histologic signs of arthritis were recorded and compared with those in C57BL/6 mice deficient in the IL-22 gene (IL-22(-/-)). Humoral and cellular immune responses against CII were analyzed. In vitro osteoclastogenesis assays were performed on splenocytes. Results. Upon immunization with CII in Freund's incomplete adjuvant plus heat-killed Mycobacterium tuberculosis, sera from C57BL/6 mice were found to contain high levels of IL-22, and the specific IL-22RI was expressed in lymphoid tissue, including splenocytes. IL-22(-/-) mice were less susceptible to CIA than were wild-type mice, as evidenced by their decreased incidence of arthritis and decreased pannus formation. Remarkably, the less severe form of arthritis in IL-22(-/-) mice was associated with increased production of CII-specific and total IgG antibodies, whereas cellular CII responses were unchanged. In vitro, IL-22 was found to promote osteoclastogenesis, a process that might contribute to its proinflammatory activity in CIA. Conclusion. Endogenous IL-22 plays a proinflammatory role in CIA in C57BL/6 mice. Our data also indicate that IL-22 promotes osteoclastogenesis and regulates antibody production.

  • Interleukin 22 forms dimers that are recognized by two Interleukin 22r1 receptor chains
    Biophysical Journal, 2008
    Co-Authors: Mario De Oliveira Neto, Jeanchristophe Renauld, Didier Colau, Laure Dumoutier, Jose Ribamar Ferreira, Hannes Fischer, Alessandro S Nascimento, A F Craievich, Igor Polikarpov
    Abstract:

    Interleukin-22 (IL-22) is a class 2 cytokine whose primary structure is similar to that of Interleukin 10 (IL-10) and interferon-gamma (IFN-gamma). IL-22 induction during acute phase immune response indicates its involvement in mechanisms of inflammation. Structurally different from IL-10 and a number of other members of IL-10 family, which form intertwined inseparable V-shaped dimers of two identical polypeptide chains, a single polypeptide chain of IL-22 folds on itself in a relatively globular structure. Here we present evidence, based on native gel electrophoresis, glutaraldehyde cross-linking, dynamic light scattering, and small angle x-ray scattering experiments, that human IL-22 forms dimers and tetramers in solution under protein concentrations assessable by these experiments. Unexpectedly, low-resolution molecular shape of IL-22 dimers is strikingly similar to that of IL-10 and other intertwined cytokine dimeric forms. Furthermore, we determine an ab initio molecular shape of the IL-22/IL-22R1 complex which reveals the V-shaped IL-22 dimer interacting with two cognate IL-22R1 molecules. Based on this collective evidence, we argue that dimerization might be a common mechanism of all class 2 cytokines for the molecular recognition with their respective membrane receptor. We also speculate that the IL-22 tetramer formation could represent a way to store the cytokine in nonactive form at high concentrations that could be readily converted into functionally active monomers and dimers upon interaction with the cognate cellular receptors.

  • Interleukin 22 il 22 activates the jak stat erk jnk and p38 map kinase pathways in a rat hepatoma cell line pathways that are shared with and distinct from il 10
    Journal of Biological Chemistry, 2002
    Co-Authors: Diane Lejeune, Laure Dumoutier, Stefan N Constantinescu, Wiebe Kruijer, Jan Jacob Schuringa, Jeanchristophe Renauld
    Abstract:

    IL (Interleukin)-22 is an IL-10-related cytokine; its main biological activity known thus far is the induction of acute phase reactants in liver and pancreas. IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called ZcytoR11/CRF2-9) and IL-10Rbeta (CRF2-4), which is also involved in IL-10 signaling. In this report, we analyzed the signal transduction pathways activated in response to IL-22 in a rat hepatoma cell line, H4IIE. We found that IL-22 induces activation of JAK1 and Tyk2 but not JAK2, as well as phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, extending the similarities between IL-22 and IL-10. However our results unraveled some differences between IL-22 and IL-10 signaling. Using antibodies specific for the phosphorylated form of MEK1/2, ERK1/2, p90RSK, JNK, and p38 kinase, we showed that IL-22 activates the three major MAPK,PK pathways. IL-22 also induced serine phosphorylation of STAT3 on Ser(727). This effect, which is not shared with IL-10, was only marginally affected by MEK1/2 inhibitors, indicating that other pathways might be involved. Finally, by overexpressing a STAT3 S727A mutant, we showed that serine phosphorylation is required to achieve maximum transactivation of a STAT responsive promoter upon IL-22 stimulation.

Wenjing Zai - One of the best experts on this subject based on the ideXlab platform.

  • Interleukin 22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury
    Theranostics, 2020
    Co-Authors: Wei Chen, Jiajun Fan, Xian Zeng, Xuyao Zhang, Jingyun Luan, Wenjing Zai, Yichen Wang, Yilan Shen
    Abstract:

    Rationale: Interleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Methods: Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Utilizing cell biological, molecular, and biochemical approaches, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. Results: IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial dysfunction. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Conclusions: Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases.

  • Interleukin 22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury
    bioRxiv, 2020
    Co-Authors: Wei Chen, Yilan Shen, Jiajun Fan, Xuyao Zhang, Jingyun Luan, Wenjing Zai, Yichen Wang
    Abstract:

    Interleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Specifically, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases. Graphical AbstractOur works demonstrate a critical role of IL-22 in regulating hepatocellular metabolism to treat liver injury via activating STAT3-lncRNA H19-AMPK-AKT-mTOR axis. These findings describe a novel mechanism underscoring the regulation of metabolic states of hepatocytes by IL-22 during liver injury with potentially broad therapeutic insights. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/892927v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@c6308corg.highwire.dtl.DTLVardef@19d6e17org.highwire.dtl.DTLVardef@a6e661org.highwire.dtl.DTLVardef@15f129e_HPS_FORMAT_FIGEXP M_FIG C_FIG

  • targeted Interleukin 22 gene delivery in the liver by polymetformin and penetratin based hybrid nanoparticles to treat nonalcoholic fatty liver disease
    ACS Applied Materials & Interfaces, 2019
    Co-Authors: Wenjing Zai, Wei Chen, Jiajun Fan, Xuyao Zhang, Jingyun Luan, Xin Jin, Shijie Tang, Xiaobin Mei, Qiang Hao, Hongrui Liu
    Abstract:

    Nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease, and there is currently no available treatment strategy. Interleukin-22 (IL-22) has been recognized as a promising agent for alleviating NAFLD, but the efficacy of IL-22 is far from satisfactory because safe dose of IL-22 elicited limited improvement, whereas higher concentration might induce serious side effects and off-target toxicities. Thus, targeted and sustained expression of IL-22 in the liver is necessary. To meet the challenge, we elaborately developed a novel polymetformin carrier by conjugating biguanide to chitosan, termed chitosan–metformin (CM), which could exert advanced gene delivery efficiency and possess intrinsic therapeutic efficacy from metformin for NAFLD. CM accompanied with penetratin and DSPE-PEG2000 could self-assemble to form stable nanocomplexes with IL-22 gene via electrostatic interaction. This nanoparticle (CDPIA) exerted desirable particle size at ∼100 nm, fine morphology, and efficient...

  • Targeted Interleukin-22 Gene Delivery in the Liver by Polymetformin and Penetratin-Based Hybrid Nanoparticles to Treat Nonalcoholic Fatty Liver Disease
    2019
    Co-Authors: Wenjing Zai, Wei Chen, Jiajun Fan, Xuyao Zhang, Jingyun Luan, Xin Jin, Shijie Tang, Xiaobin Mei, Qiang Hao
    Abstract:

    Nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease, and there is currently no available treatment strategy. Interleukin-22 (IL-22) has been recognized as a promising agent for alleviating NAFLD, but the efficacy of IL-22 is far from satisfactory because safe dose of IL-22 elicited limited improvement, whereas higher concentration might induce serious side effects and off-target toxicities. Thus, targeted and sustained expression of IL-22 in the liver is necessary. To meet the challenge, we elaborately developed a novel polymetformin carrier by conjugating biguanide to chitosan, termed chitosan–metformin (CM), which could exert advanced gene delivery efficiency and possess intrinsic therapeutic efficacy from metformin for NAFLD. CM accompanied with penetratin and DSPE-PEG2000 could self-assemble to form stable nanocomplexes with IL-22 gene via electrostatic interaction. This nanoparticle (CDPIA) exerted desirable particle size at ∼100 nm, fine morphology, and efficient cellular internalization. Furthermore, CDPIA also demonstrated a unique superiority in endosomal escape capacity and satisfactory biocompatibility as well as predominant liver accumulation. Most importantly, CDPIA distinctly alleviated hepatic steatosis, restored insulin sensitivity, and improved metabolic syndrome in high-fat-diet-fed mice model. This liver-targeted delivery of IL-22 activated STAT3/Erk1/2 and Nrf2/SOD1 signaling transductions as well as modulated lipid-metabolism-related gene expression. These findings altogether demonstrated that the polymetformin and penetratin-based hybrid nanoparticles could be exploited as a novel safe and efficient strategy for the improvement of NAFLD

  • in vivo hepatocellular expression of Interleukin 22 using penetratin based hybrid nanoparticles as potential anti hepatitis therapeutics
    Biomaterials, 2018
    Co-Authors: Wei Chen, Jiajun Fan, Xuyao Zhang, Jingyun Luan, Wenjing Zai, Yichen Wang, Gang Wei, Shaofei Wang, Yanxu Liang, Yanyang Nan
    Abstract:

    Hepatocellular injury is the pathological hallmark of hepatitis and a crucial driver for the progression of liver diseases, while the treatment options are commonly restricted. Interleukin-22 (IL-22) has attracted special attention as a potent survival factor for hepatocytes that both prevents and repairs the injury of hepatocytes through activation of STAT3 signaling pathway. We hypothesized that the ability to generate potent expression of IL-22 locally for the treatment of severe hepatocellular injury in hepatitis was a promising strategy to enhance efficacy and overcome off-target effects. Accordingly, we developed a polypeptide penetratin-based hybrid nanoparticle system (PDPIA) carrying IL-22 gene by a self-assembly process. This nanocomplex modified with penetratin featured direct translocation across the cellular or endosomal membrane but mild zeta-potential to facilitate the high cellular internalization and endosomal escape of the gene cargos as well as scarcely Kupffer cells uptake. More importantly, PDPIA afforded preferential liver accumulation and predominant hepatocytes internalization following systemic administration, which showed pharmacologically suitable organ and sub-organ-selective properties. Subsequent studies confirmed a considerable protective role of PDPIA in a model of severe hepatitis induced by concanavalin A, evidenced by reduced hepatocellular injury and evaded immune response. The locally expressed IL-22 by PDPIA activated STAT3/Erk signal transduction, and thus promoted hepatocyte regeneration, inhibited reactive oxygen species (ROS) accumulation as well as prevented the dysfunction of mitochondrial. In addition, this system did not manifest side effects or systemic toxicity in mice. Collectively, the high versatility of PDPIA rendered its promising applications might be an effective agent to treat various hepatic disorders.