Dataset Information

RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease.

ABSTRACT: Retinoic acid inducible-gene I (RIG-I) functions as one of the major sensors of RNA viruses. DDX58, which encodes the RIG-I protein, has been newly identified as a susceptibility gene in psoriasis. Here, we show that the activation of RIG-I by 5'ppp-dsRNA, its synthetic ligand, directly causes the production of IL-23 and triggers psoriasis-like skin disease in mice. Repeated injections of IL-23 to the ears failed to induce IL-23 production and a full psoriasis-like skin phenotype, in either germ-free or RIG-I-deficient mice. RIG-I is also critical for a full development of skin inflammation in imiquimod (IMQ)-induced psoriasis-like mouse model. Furthermore, RIG-I-mediated endogenous IL-23 production was mainly confined to the CD11c+ dendritic cells (DCs) via nuclear factor-kappa B (NF-?B) signaling, and stimulated RIG-I expression in an auto-regulatory feedback loop. Thus, our data suggest that the dysregulation in the antiviral immune responses of hosts through the innate pattern recognition receptors may trigger the skin inflammatory conditions in the pathophysiology of psoriasis.

SUBMITTER: Zhu H

PROVIDER: S-EPMC5412807 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

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RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease.

Zhu Huiyuan H Lou Fangzhou F Yin Qianqian Q Gao Yuanyuan Y Sun Yang Y Bai Jing J Xu Zhenyao Z Liu Zhaoyuan Z Cai Wei W Ke Fang F Zhang Lingyun L Zhou Hong H Wang Hong H Wang Gang G Chen Xiang X Zhang Hongxin H Wang Zhugang Z Ginhoux Florent F Lu Chuanjian C Su Bing B Wang Honglin H

EMBO molecular medicine 20170501 5

Retinoic acid inducible-gene I (RIG-I) functions as one of the major sensors of RNA viruses. <i>DDX58</i>, which encodes the RIG-I protein, has been newly identified as a susceptibility gene in psoriasis. Here, we show that the activation of RIG-I by 5'ppp-dsRNA, its synthetic ligand, directly causes the production of IL-23 and triggers psoriasis-like skin disease in mice. Repeated injections of IL-23 to the ears failed to induce IL-23 production and a full psoriasis-like skin phenotype, in eith ...[more]

PMID: 28377495

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Project description:Pathogenic hantaviruses, genus Orthohantaviridae, are maintained in rodent reservoirs with zoonotic transmission to humans occurring through inhalation of rodent excreta. Hantavirus disease in humans is characterized by localized vascular leakage and elevated levels of circulating proinflammatory cytokines. Despite the constant potential for deadly zoonotic transmission to humans, specific virus-host interactions of hantaviruses that lead to innate immune activation, and how these processes impart disease, remain unclear. In this study, we examined the mechanisms of viral recognition and innate immune activation of Hantaan orthohantavirus (HTNV) infection. We identified the RIG-I-like receptor (RLR) pathway as essential for innate immune activation, interferon (IFN) production, and interferon stimulated gene (ISG) expression in response to HTNV infection in human endothelial cells, and in murine cells representative of a non-reservoir host. Our results demonstrate that innate immune activation and signaling through the RLR pathway depends on viral replication wherein the host response can significantly restrict replication in target cells in a manner dependent on the type 1 interferon receptor (IFNAR). Importantly, following HTNV infection of a non-reservoir host murine model, IFNAR-deficient mice had higher viral loads, increased persistence, and greater viral dissemination to lung, spleen, and kidney compared to wild-type animals. Surprisingly, this response was MAVS independent in vivo. Innate immune profiling in these tissues demonstrates that HTNV infection triggers expression of IFN-regulated cytokines early during infection. We conclude that the RLR pathway is essential for recognition of HTNV infection to direct innate immune activation and control of viral replication in vitro, and that additional virus sensing and innate immune response pathways of IFN and cytokine regulation contribute to control of HTNV in vivo. These results reveal a critical role for innate immune regulation in driving divergent outcomes of HTNV infection, and serve to inform studies to identify therapeutic targets to alleviate human hantavirus disease.

Dataset Information

RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease.

Publications

RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease.

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