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DHX15 is required to control RNA virus-induced intestinal inflammation.

ABSTRACT: RNA helicases play critical roles in various biological processes, including serving as viral RNA sensors in innate immunity. Here, we find that RNA helicase DEAH-box helicase 15 (DHX15) is essential for type I interferon (IFN-I, IFN-β), type III IFN (IFN-λ3), and inflammasome-derived cytokine IL-18 production by intestinal epithelial cells (IECs) in response to poly I:C and RNA viruses with preference of enteric RNA viruses, but not DNA virus. Importantly, we generate IEC-specific Dhx15-knockout mice and demonstrate that DHX15 is required for controlling intestinal inflammation induced by enteric RNA virus rotavirus in suckling mice and reovirus in adult mice in vivo, which owes to impaired IFN-β, IFN-λ3, and IL-18 production in IECs from Dhx15-deficient mice. Mechanistically, DHX15 interacts with NLRP6 to trigger NLRP6 inflammasome assembly and activation for inducing IL-18 secretion in IECs. Collectively, our report reveals critical roles for DHX15 in sensing enteric RNA viruses in IECs and controlling intestinal inflammation.

SUBMITTER: Xing J

PROVIDER: S-EPMC8276442 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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DHX15 is required to control RNA virus-induced intestinal inflammation.

Xing Junji J Zhou Xiaojing X Fang Mingli M Zhang Evan E Minze Laurie J LJ Zhang Zhiqiang Z

Cell reports 20210601 12

RNA helicases play critical roles in various biological processes, including serving as viral RNA sensors in innate immunity. Here, we find that RNA helicase DEAH-box helicase 15 (DHX15) is essential for type I interferon (IFN-I, IFN-β), type III IFN (IFN-λ3), and inflammasome-derived cytokine IL-18 production by intestinal epithelial cells (IECs) in response to poly I:C and RNA viruses with preference of enteric RNA viruses, but not DNA virus. Importantly, we generate IEC-specific Dhx15-knockou ...[more]

PMID: 34161762

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Project description:Background & aimsLoss-of-function variants in the laccase domain containing 1 (LACC1) gene are associated with immune-mediated diseases, including inflammatory bowel disease. It is not clear how LACC1 balances defenses against intestinal bacteria vs intestinal inflammation or what cells are responsible for this balance in humans or mice.MethodsLacc1-/- mice and mice with myeloid-specific disruption of Lacc1 (Lacc1Δmye) were given oral Salmonella Typhimurium or dextran sodium sulfate. CD45RBhiCD4+T cells were transferred to Lacc1-/-Rag2-/- mice to induce colitis. Organs were collected and analyzed by histology and protein expression. Bone marrow-derived macrophages and dendritic cells, lamina propria macrophages, and mesenteric lymph node dendritic cells were examined. We performed assays to measure intestinal permeability, cell subsets, bacterial uptake and clearance, reactive oxygen species, nitrite production, autophagy, signaling, messenger RNA, and cytokine levels.ResultsLacc1-/- mice developed more severe T-cell transfer colitis than wild-type mice and had an increased burden of bacteria in intestinal lymphoid organs, which expressed lower levels of T helper (Th) 1 and Th17 cytokines and higher levels of Th2 cytokines. Intestinal lymphoid organs from mice with deletion of LACC1 had an increased burden of bacteria after oral administration of S Typhimurium and after administration of dextran sodium sulfate compared with wild-type mice. In macrophages, expression of LACC1 was required for toll-like receptor-induced uptake of bacteria, which required PDK1, and of mitogen-activated protein kinase (MAPK)- and nuclear factor κB-dependent induction of reactive oxygen species, reactive nitrogen species, and autophagy. Expression of LACC1 by dendritic cells was required for increasing expression of Th1 and Th17 cytokines and reducing expression of Th2 cytokines upon coculture with CD4+ T cells. Mice with LACC1-deficient myeloid cells had an increased burden of bacteria and altered T-cell cytokines in intestinal lymphoid organs, similar to Lacc1-/- mice. Complementation of cytokines produced by myeloid cells to cocultures of LACC1-deficient myeloid cells and wild-type CD4+ T cells restored T-cell cytokine regulation. When S Typhimurium-infected Lacc1Δmye mice were injected with these myeloid cell-derived cytokines, intestinal tissues increased production of Th1 and Th17 cytokines, and bacteria were reduced.ConclusionsDisruption of Lacc1 in mice increases the burden of bacteria in intestinal lymphoid organs and intestinal inflammation after induction of chronic colitis. LACC1 expression by myeloid cells in mice is required to clear bacteria and to regulate adaptive T-cell responses against microbes.

Project description:The inflammatory response to viral infection in humans is a dynamic process with complex cell interactions that are governed by the immune system and influenced by both host and viral factors. Due to this complexity, the relative contributions of the virus and host factors are best studied in vivo using animal models. In this review, we describe how the zebrafish (Danio rerio) has been used as a powerful model to study host-virus interactions and inflammation by combining robust forward and reverse genetic tools with in vivo imaging of transparent embryos and larvae. The innate immune system has an essential role in the initial inflammatory response to viral infection. Focused studies of the innate immune response to viral infection are possible using the zebrafish model as there is a 4-6 week timeframe during development where they have a functional innate immune system dominated by neutrophils and macrophages. During this timeframe, zebrafish lack a functional adaptive immune system, so it is possible to study the innate immune response in isolation. Sequencing of the zebrafish genome has revealed significant genetic conservation with the human genome, and multiple studies have revealed both functional conservation of genes, including those critical to host cell infection and host cell inflammatory response. In addition to studying several fish viruses, zebrafish infection models have been developed for several human viruses, including influenza A, noroviruses, chikungunya, Zika, dengue, herpes simplex virus type 1, Sindbis, and hepatitis C virus. The development of these diverse viral infection models, coupled with the inherent strengths of the zebrafish model, particularly as it relates to our understanding of macrophage and neutrophil biology, offers opportunities for far more intensive studies aimed at understanding conserved host responses to viral infection. In this context, we review aspects relating to the evolution of innate immunity, including the evolution of viral pattern recognition receptors, interferons and interferon receptors, and non-coding RNAs.

Dataset Information

DHX15 is required to control RNA virus-induced intestinal inflammation.

Publications

DHX15 is required to control RNA virus-induced intestinal inflammation.

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