<i>Drosophila</i>Ras/MAPK signalling regulates innate immune responses in immune and intestinal stem cells

Ragab, Anan; Buechling, Tina; Gesellchen, Viola; Spirohn, Kerstin; Boettcher, Anna Lisa; Boutros, Michael

doi:10.1038/emboj.2011.4

Cited by 117 publications

(91 citation statements)

References 72 publications

(101 reference statements)

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“…Instead, the Imd pathway is subject to other negative feedback mechanisms, such as the rapid induction of a gene called pirk (90,91). Pirk expression appears to be induced by the Ras/MAPK pathway as well, suggesting that Ras/MAPK signaling functions in immunity by negatively regulating the Imd pathway (92). Pirk interacts with the receptors PGRP-LC and PCRP-LE and the adaptor protein Imd, thus likely interrupting signal transduction at the receptor complex (91,93,94).…”

Section: Regulation Of the Imd Signaling Pathwaymentioning

confidence: 99%

The Drosophila Imd Signaling Pathway

Myllymäki

Valanne

Rämet

2014

The Journal of Immunology

463

357

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The fruit fly, Drosophila melanogaster, has helped us to understand how innate immunity is activated. In addition to the Toll receptor and the Toll signaling pathway, the Drosophila immune response is regulated by another evolutionarily conserved signaling cascade, the immune deficiency (Imd) pathway, which activates NF-κB. In fact, the Imd pathway controls the expression of most of the antimicrobial peptides in Drosophila; thus, it is indispensable for normal immunity in flies. In this article, we review the current literature on the Drosophila Imd pathway, with special emphasis on its role in the (patho)physiology of different organs. We discuss the systemic response, as well as local responses, in the epithelial and mucosal surfaces and the nervous system.

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Section: Regulation Of the Imd Signaling Pathwaymentioning

confidence: 99%

The Drosophila Imd Signaling Pathway

Myllymäki

Valanne

Rämet

2014

The Journal of Immunology

463

357

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“…For example, activity of the Ras/MAPK pathway negatively regulates IMD-Relish signaling (3). Signaling by the small molecule NO can promote Relish activity independently of IMD (4).…”

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confidence: 99%

Specific Calcineurin Isoforms Are Involved in Drosophila Toll Immune Signaling

Dijkers

2015

The Journal of Immunology

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Because excessive or inadequate responses can be detrimental, immune responses to infection require appropriate regulation. Networks of signaling pathways establish versatility of immune responses. Drosophila melanogaster is a powerful model organism for dissecting conserved innate immune responses to infection. For example, the Toll pathway, which promotes activation of NF-κB transcription factors Dorsal/Dorsal-related immune factor (Dif), was first identified in Drosophila. Together with the IMD pathway, acting upstream of NF-κB transcription factor Relish, these pathways constitute a central immune signaling network. Inputs in these pathways contribute to specific and appropriate responses to microbial insults. Relish activity during infection is modulated by Ca2+-dependent serine/threonine phosphatase calcineurin, an important target of immunosuppressants in transplantation biology. Only one of the three Drosophila calcineurin isoforms, calcineurin A1, acts on Relish during infection. However, it is not known whether there is a role for calcineurin in Dorsal/Dif immune signaling. In this article, we demonstrate involvement of specific calcineurin isoforms, protein phosphatase at 14D (Pp2B-14D)/calcineurin A at 14F (CanA-14F), in Toll-mediated immune signaling. These isoforms do not affect IMD signaling. In cell culture, pharmacological inhibition of calcineurin or RNA interference against homologous calcineurin isoforms Pp2B-14D/CanA-14F, but not against isoform calcineurin A1, decreased Toll-dependent Dorsal/Dif activity. A Pp2B-14D gain-of-function transgene promoted Dorsal nuclear translocation and Dorsal/Dif activity. In vivo, Pp2B-14D/CanA-14F RNA interference attenuated the Dorsal/Dif-dependent response to infection without affecting the Relish-dependent response. Altogether, these data identify a novel input, calcineurin, in Toll immune signaling and demonstrate involvement of specific calcineurin isoforms in Drosophila NF-κB signaling.

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“…The magnitude of inflammatory signals expressed by the immune system (ILC, T cells, macrophages, dendritic cells) or the intestinal cells associated with IBD can be expanded to include tumor necrosis factors (TNFSF) 8/9/11/14/15 and receptors (Gunther et al 2011) ATG4B (Cabrera et al 2013); IRGM1 (Henry et al 2007); ATG16L1 (Saitoh et al 2008); RIPK3 (Gunther et al 2011) ATG1, ATG6 (Wu et al 2009a) Innate immunity NF-kB, TNF-α (Plevy et al 1997 (Buchon et al 2009b, Lemaitre et al 1995; Jak-Stat (Buchon et al 2009b); Ras (Ragab et al 2011); Toll (Lemaitre et al 1996); bbg (Bonnay et al 2013 (Jiang et al 2011a); Wnt, APC Oxidative stress NOS2 (Singer et al 1996;Dhillon et al 2014); Duox2 (Wu et al 2013 (Jones et al 2013) dDuox (Ha et al 2009); dNox (Jones et al 2013) (continued) 7 Parallels Between Mammals and Flies in Inflammatory Bowel Disease (Makitalo et al 2009…”

Section: Genetic Predispositionmentioning

confidence: 99%

Parallels Between Mammals and Flies in Inflammatory Bowel Disease

Christofi

Apidianakis

2015

Life Extension

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The intestinal hologenome lies at the center of intestinal homeostasis and disease. It is the sum of the host genome and the intestinal microbiome. During the last decade we came to appreciate the pivotal role of the microbiome in intestinal inflammation and concomitant diseases. Moreover environmental factors, predominantly diet, affect the microbiome and the host immune responses. Thus manipulation of intestinal microbiota and environmental factors are rightfully the focus of current research. The study of the hologenome necessitates not only clinical assessments but also the use of model organisms, for example, mice and flies. Despite the limitations imposed by the evolutionary distance between flies and mammals, Drosophila research provided us during the last few years with a wealth of information regarding intestinal inflammation and the role of microbiota. Conserved aspects of intestinal homeostasis and disease between flies and mice, for example in signalling pathways, the intestinal defence responses and the role of microbiota, consolidate and may advance the principles that govern intestinal inflammation in humans.

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DrosophilaRas/MAPK signalling regulates innate immune responses in immune and intestinal stem cells

Cited by 117 publications

References 72 publications

The Drosophila Imd Signaling Pathway

The Drosophila Imd Signaling Pathway

Specific Calcineurin Isoforms Are Involved in Drosophila Toll Immune Signaling

Parallels Between Mammals and Flies in Inflammatory Bowel Disease

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