ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS–STING

Aden, Konrad; Tran, Florian; Ito, Go; Sheibani-Tezerji, Raheleh; Lipinski, Simone; Kuiper, J.J.W.; Tschurtschenthaler, Markus; Saveljeva, Svetlana; Bhattacharyya, Joya; Häsler, Robert; Bartsch, Kareen; Luzius, Anne; Jentzsch, Marlene; Falk-Paulsen, Maren; Stengel, Stephanie T.; Welz, Lina; Schwarzer, Robin; Rabe, Björn; Barchet, Winfried; Krautwald, Stefan; Hartmann, Gunther; Pasparakis, Manolis; Blumberg, Richard S.; Schreiber, Stefan; Kaser, Arthur; Rosenstiel, Philip

doi:10.1084/jem.20171029

Cited by 141 publications

(144 citation statements)

References 72 publications

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“…Secondly, therapeutic targeting of these metabolic processes in hepatocytes therefore can be directly favorable to the prevention or treatment of liver injury diseases. Finally, with recombinant IL-22 proteins at present being explored as potential therapeutic strategies in human diseases as severe alcoholic hepatitis, graft-versus-host disease and inflammatory bowel disease, our research may have momentous clinical significances [18][19]37].…”

Section: Discussionmentioning

confidence: 99%

“…Despite growing evidence suggests that IL-22 is a promising antidote to treat various hepatic disorders, the molecular basis of the liver protective activities of IL-22 needs to be fully characterized. Uncovering the underlying mechanisms of IL-22 is necessary both for understanding how IL-22 acts to prevent liver injury and for identifying critical processes as well as molecular regulators involved in addressing liver injury [18][19].…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Chen

Zai

Fan

et al. 2020

Preprint

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AbstractInterleukin 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Chen

Zai

Fan

et al. 2020

Preprint

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“…Indeed, Mfs from inflamed Crohn's disease tissue induced less IL-22 secretion by innate lymphoid cells than those from quiescent area (248), and blood monocytes reduced epithelial barrier efficiency in vitro by altering the structure and function of tight junctions (271). Finally, intestinal Mfs from IBD patients had increased ROS production (291), which can also contribute to epithelial injury (292).…”

Section: Function Of Intestinal Mucosa Macrophagesmentioning

confidence: 99%

Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

Caër

Wick

2020

Front. Immunol.

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Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex immune-mediated disease of the gastrointestinal tract that increases morbidity and negatively influences the quality of life. Intestinal mononuclear phagocytes (MNPs) have a crucial role in maintaining epithelial barrier integrity while controlling pathogen invasion by activating an appropriate immune response. However, in genetically predisposed individuals, uncontrolled immune activation to intestinal flora is thought to underlie the chronic mucosal inflammation that can ultimately result in IBD. Thus, MNPs are involved in fine-tuning mucosal immune system responsiveness and have a critical role in maintaining homeostasis or, potentially, the emergence of IBD. MNPs include monocytes, macrophages and dendritic cells, which are functionally diverse but highly complementary. Despite their crucial role in maintaining intestinal homeostasis, specific functions of human MNP subsets are poorly understood, especially during diseases such as IBD. Here we review the current understanding of MNP ontogeny, as well as the recently identified human intestinal MNP subsets, and discuss their role in health and IBD.

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“…The loss of this immunologic equilibrium due to the deficiency of p62 may cause chronic inflammation and autoimmunity. The loss of another autophagy protein called ATG16L1 induces cGAS‐STING signaling during IBD in intestinal epithelial cells via IL‐22 that causes an increased ER stress and the release of type 1 IFNs . The increased type 1 IFNs further amplifies the production of TNF‐α and contributes to the necroptotic cell death and endogenous inflammation .…”

Section: Negative Regulation Of Cgas‐sting Signaling and Its Impact Omentioning

confidence: 99%

“…The loss of another autophagy protein called ATG16L1 induces cGAS‐STING signaling during IBD in intestinal epithelial cells via IL‐22 that causes an increased ER stress and the release of type 1 IFNs . The increased type 1 IFNs further amplifies the production of TNF‐α and contributes to the necroptotic cell death and endogenous inflammation . The therapeutic targeting of STING or type 1 IFN signaling prevents the IL‐22‐induced ileal inflammation in Atg16l1ΔIEC mice.…”

Section: Negative Regulation Of Cgas‐sting Signaling and Its Impact Omentioning

confidence: 99%

A STING to inflammation and autoimmunity

Kumar

2019

Journal of Leukocyte Biology

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Various intracellular pattern recognition receptors (PRRs) recognize cytosolic pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Cyclic GMP-AMP synthase (cGAS), a cytosolic PRR, recognizes cytosolic nucleic acids including dsDNAs. The recognition of dsDNA by cGAS generates cyclic GMP-AMP (GAMP). The cGAMP is then recognized by STING generating type 1 IFNs and NF-B-mediated generation of proinflammatory cytokines and molecules. Thus, cGAS-STING signaling mediated recognition of cytosolic dsDNA causing the induction of type 1 IFNs plays a crucial role in innate immunity against cytosolic pathogens, PAMPs, and DAMPs. The overactivation of this system may lead to the development of autoinflammation and autoimmune diseases. The article opens with the introduction of different PRRs involved in the intracellular recognition of dsDNA and gives a brief introduction of cGAS-STING signaling. The second section briefly describes cGAS as intracellular PRR required to recognize intracellular nucleic acids (dsDNA and CDNs) and the formation of cGAMP. The cGAMP acts as a second messenger to activate STING-and TANK-binding kinase 1-mediated generation of type 1 IFNs and the activation of NF-B. The third section of the article describes the role of cGAS-STING signaling in the induction of autoinflammation and various autoimmune diseases. The subsequent fourth section describes both chemical compounds developed and the endogenous negative regulators of cGAS-STING signaling required for its regulation. Therapeutic targeting of cGAS-STING signaling could offer new ways to treat inflammatory and autoimmune diseases. K E Y W O R D S

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ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS–STING

Abstract: Dysregulated autophagy and ER stress are involved in the etiology of human IBD. Aden et al. show that loss of ATG16L1 function renders intestinal epithelial cells vulnerable to IL-22–induced ER stress and necroptosis via STING signaling, which induces ileal inflammation in vivo.

Cited by 141 publications

References 72 publications

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

A STING to inflammation and autoimmunity

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