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Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis.

ABSTRACT: Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. M?s (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 ? release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD(+):NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in M?s from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient M?s leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of M?s is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in M?s may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

SUBMITTER: Lee HY

PROVIDER: S-EPMC4968230 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis.

Lee Hae-Youn HY Kim Jinyoung J Quan Wenying W Lee June-Chul JC Kim Min-Soo MS Kim Seok-Hyung SH Bae Jin-Woo JW Hur Kyu Yeon KY Lee Myung-Shik MS

Autophagy 20160623 8

Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mi ...[more]

PMID: 27337687

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Project description:The endoribonuclease RNase-L is a type-I interferon (IFN)-regulated component of the innate immune response that functions in antiviral, antibacterial, and antiproliferative activities. RNase-L produces RNA agonists of RIG-I-like receptors, sensors of cytosolic pathogen-associated RNAs that induce cytokines including IFN-?. IFN-? and RIG-I-like receptors signaling mediate protective responses against experimental colitis and colitis-associated cancer and contribute to gastrointestinal homeostasis. Therefore, we investigated a role for RNase-L in murine colitis and colitis-associated cancer and its association with RIG-I-like receptors signaling in response to bacterial RNA.Colitis was induced in wild type-deficient and RNase-L-deficient mice (RNase-L?/?) by administration of dextran sulfate sodium (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM). Histological analysis and immunohistochemistry were performed on colon tissue to analyze immune cell infiltration and tissue damage after induction of colitis. Expression of cytokines was measured by quantitative real-time-PCR and ELISA.DSS-treated RNase-L?/? mice exhibited a significantly higher clinical score, delayed leukocyte infiltration, reduced expression of IFN-?, tumor necrosis factor ?, interleukin-1?, and interleukin-18 at early times post-DSS exposure, and increased mortality as compared with wild-type mice. DSS/AOM-treated RNase-L?/? mice displayed an increased tumor burden. Bacterial RNA triggered IFN-? production in an RNase-L-dependent manner and provided a potential mechanism by which RNase-L contributes to the gastrointestinal immune response to microbiota and protects against experimental colitis and colitis-associated cancer.RNase-L promotes the innate immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer. The RNase-L-dependent production of IFN-? stimulated by bacterial RNA may be a mechanism to protect against gastrointestinal inflammatory disease.

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Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis.

Publications

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis.

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