RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury

Fischer, Julius; Bscheider, Michael; Eisenkolb, Gabriel; Lin, Chih-Hsu; Wintges, Alexander; Otten, Vera; Lindemans, Caroline A.; Heidegger, Simon; Rudelius, Martina; Monette, Sébastien; Rodriguez, Kori A. Porosnicu; Calafiore, Marco; Liebermann, Sophie; Liu, Chen; Lienenklaus, Stefan; Kalinke, Ulrich; Ruland, Jürgen; Peschel, Christian; Shono, Yusuke; Docampo, Melissa D.; Velardi, Enrico; Jenq, Robert R.; Hanash, Alan M.; Dudakov, Jarrod A; Haas, Tobias; Brink, Marcel R.M. van den; Poeck, Hendrik

doi:10.1126/scitranslmed.aag2513

Cited by 111 publications

(118 citation statements)

References 46 publications

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“…Our results are complementary to the role of MAVS in monitoring intestinal commensal bacteria and maintaining intestinal tissue homeostasis described by Li and colleagues (13). Moreover, the RIG-I/MAVS pathway activation and subsequent IFN-I signaling were recently shown to maintain gut epithelial barrier integrity (22). RIG-I was described as being constitutively expressed at the apical surface of intestinal human biopsies (23).…”

Section: Discussion/conclusionsupporting

confidence: 82%

MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype

Plantamura

Dzutsev

Chamaillard

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Prominent changes in the gut microbiota (referred to as “dysbiosis”) play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I–like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology. Cohousing and fecal transplantation experiments revealed that the dysbiotic microbiota of Mavs−/− mice conferred a proallergic phenotype that is communicable to wild-type mice. DTH sensitization coincided with increased intestinal permeability and bacterial translocation within lymphoid organs that enhanced DTH severity. Collectively, we unveiled an unexpected impact of RIG-I–like signaling on the gut microbiota with consequences on allergic skin disease outcome. Primarily, these data indicate that manipulating the gut microbiota may help in the development of therapeutic strategies for the treatment of human allergic skin pathologies.

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Section: Discussion/conclusionsupporting

confidence: 82%

MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype

Plantamura

Dzutsev

Chamaillard

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Complete loss of IFN-γ, paradoxically, caused more severe GVHD, potentially because of the loss of antiinflammatory effects of donor-derived IFN-γ and IFN-γ receptor signaling (6,8,55,56). Type I IFNs have been shown to reduce (57,58) or promote (59) GVHD while playing an important role in contributing to donor-derived GVL effects. Similarly, IL-17-producing Th17 cells have been shown to promote aGVHD; however, absence of IL-17 has been shown to promote aGVHD by augmenting Th1 responses (6,7,10,51,60,61).…”

Section: Discussionmentioning

confidence: 99%

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

Snyder¹,

Zitzer²,

Gao³

et al. 2020

JCI Insight

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“…Experiments were performed essentially as previously described and are summarized in Supporting Materials.…”

Section: Methodsmentioning

confidence: 99%

A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

et al. 2017

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The NF-κB regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4 and CD8 donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T-cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-γ and systemic inflammation was elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20 T cells. Still, A20-deficient T cells, activated either through T cell receptor-dependent or -independent mechanisms, were less viable than control A20 T cells, highlighting that A20 balances both, T-cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T-cell-mediated inflammatory diseases like GVHD.

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RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury

Cited by 111 publications

References 46 publications

MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype

MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

A20 deletion in T cells modulates acute graft‐versus‐host disease in mice

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