Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome.

Busillo, John M.; Azzam, Kathleen M.; Cidlowski, John A.

doi:10.1074/jbc.a111.275370

Cited by 26 publications

(29 citation statements)

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“…Thus, it is conceivable that the regulatory network delineated in this study is part of a neuroendocrine-immune axis, whereby stress-induced elevation of the steroid hormone 20E drives elevated PGRP-LC expression and primes all the AMP genes, enabling a more robust immune response during times of stress. Although the direction of this regulation is opposite of that observed in mammals, where stress-induced glucocorticoids are best known to pharmacologically reduce the inflammatory response, several recent reports have clearly shown that glucocorticoids, when produced at physiological levels, actually induce the expression of innate immune receptors like TLR2 and NLRP3 (Shuto et al, 2002;Hermoso et al, 2004;Sakai et al, 2004;Busillo et al, 2011), very similar to the 20E-PGRP-LC axis demonstrated here. Thus, a profound but poorly understood conservation in the neuroendocrine regulation of innate immunity may exist in invertebrates and mammals.…”

Section: Discussionsupporting

confidence: 65%

“…In the context of immunity, pharmacologic application of glucocorticoids has multiple potent anti-inflammatory effects on immune cells (Necela and Cidlowski, 2004;Sternberg, 2006). In addition to the well-known immunosuppressive effects of glucocorticoids, many studies have revealed that physiological levels of glucocorticoids actually enhance the immune and inflammatory response (Galon et al, 2002;Shuto et al, 2002;Goulding, 2004;Hermoso et al, 2004;Sakai et al, 2004;Dhabhar, 2009;Busillo et al, 2011). Several other nuclear hormone receptors, including estrogen receptors (ERs), peroxisome proliferatoractivated receptors (PPARs), vitamin D receptors (VDRs), retinoid-related orphan receptors (RORs), retinoid X receptors (RXRs) and liver X receptors (LXRs), have also been found to positively regulate innate immunity and proinflammatory cytokine expression (Tontonoz et al, 1998;Hong and Tontonoz, 2008;Jetten, 2009;Baeke et al, 2010;Nunez et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity

Rus

Flatt

Tong

et al. 2013

EMBO J

137

175

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Throughout the animal kingdom, steroid hormones have been implicated in the defense against microbial infection, but how these systemic signals control immunity is unclear. Here, we show that the steroid hormone ecdysone controls the expression of the pattern recognition receptor PGRP-LC in Drosophila, thereby tightly regulating innate immune recognition and defense against bacterial infection. We identify a group of steroid-regulated transcription factors as well as two GATA transcription factors that act as repressors and activators of the immune response and are required for the proper hormonal control of PGRP-LC expression. Together, our results demonstrate that Drosophila use complex mechanisms to modulate innate immune responses, and identify a transcriptional hierarchy that integrates steroid signalling and immunity in animals.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity

Rus

Flatt

Tong

et al. 2013

EMBO J

137

175

View full text Add to dashboard Cite

show abstract

“…In mammals, glucocorticoids are the main neuroendocrine to regulate the immune system (45). Several studies showed that stressors can rapidly result in the systemic release of glucocorticoids, and thereby alter the mammalian innate immune and inflammatory response through the glucocorticoid receptor (44,46,47). In insects, molting hormone 20E titers can also increase when they are exposed to different stressors, such as starvation, heat treatment, and sleep deprivation (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Ecdysone Titer Determined by 3DE-3β-Reductase Enhances the Immune Response in the Silkworm

Sun

Shen

Zhou

et al. 2016

The Journal of Immunology

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Although recent studies have demonstrated that 20-hydroxyecdysone (20E), one of the two most important hormones for development, could promote the insect innate immune response, how insects regulate 20E titer to affect the immunity after suffering pathogen attack remains unknown. In this study, to our knowledge, we first found that 20E titer was significantly elevated after bacterial infection in the domesticated silkworm, Bombyx mori. Furthermore, the elevated 20E enhanced the silkworm innate immune system against invading bacteria via ecdysone receptor. During immune response, the expression of the silkworm 3-dehydroecdysone-3β-reductase (3DE-3β-reductase) that converts 3DE released from prothoracic glands into ecdysone was induced. RNA interference experiments suggested that 3DE-3β-reductase is essential to upregulate the 20E titer after bacterial infection. The rescue experiments showed that injection with the recombinant 3DE-3β-reductase protein can significantly elevate the 20E concentration and modulate the expressions of the silkworm immune-related genes. Taken together, 20E titer determined by 3DE-3β-reductase enhances the silkworm defense against the bacterial infection. Thus, our findings reveal an important role of the 20E synthesis pathway from 3DE in enhancing the silkworm immune response and have profound implications for the understanding of interaction mechanisms between insect hormone and immunity.

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“…4; Table S4), which may allow early colonization and adaptation of these probiotics to the host. GR signaling leads to enhanced release of proinflammatory cytokines IL-1β, TNF-α, and IL-6, 54 hence, it may be conceivable that downregulation of GR signaling at an early stage by both LA and LGG could suppress the initial host response that otherwise prevents probiotic colonization (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

In vivo gut transcriptome responses toLactobacillus rhamnosusGG andLactobacillus acidophilusin neonatal gnotobiotic piglets

et al. 2014

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Probiotics facilitate mucosal repair and maintain gut homeostasis. They are often used in adjunct with rehydration or antibiotic therapy in enteric infections. Lactobacillus spp have been tested in infants for the prevention or treatment of various enteric conditions. however, to aid in rational strain selection for specific treatments, comprehensive studies are required to delineate and compare the specific molecules and pathways involved in a less complex but biologically relevant model (gnotobiotic pigs). here we elucidated Lactobacillus rhamnosus (LGG) and L. acidophilus (LA) specific effects on gut transcriptome responses in a neonatal gnotobiotic (Gn) pig model to simulate responses in newly colonized infants. Whole genome microarray, followed by biological pathway reconstruction, was used to investigate the host-microbe interactions in duodenum and ileum at early (day 1) and later stages (day 7) of colonization. Both LA and LGG modulated common responses related to host metabolism, gut integrity, and immunity, as well as responses unique to each strain in Gn pigs. Our data indicated that probiotic establishment and beneficial effects in the host are guided by: (1) down-regulation or upregulation of immune function-related genes in the early and later stages of colonization, respectively, and (2) alternations in metabolism of small molecules (vitamins and/or minerals) and macromolecules (carbohydrates, proteins, and lipids). Pathways related to immune modulation and carbohydrate metabolism were more affected by LGG, whereas energy and lipid metabolism-related transcriptome responses were prominently modulated by LA. These findings imply that identification of probiotic strain-specific gut responses could facilitate the rational design of probiotic-based interventions to moderate specific enteric conditions.

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Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome.

Cited by 26 publications

References 0 publications

Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity

Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity

Ecdysone Titer Determined by 3DE-3β-Reductase Enhances the Immune Response in the Silkworm

In vivo gut transcriptome responses toLactobacillus rhamnosusGG andLactobacillus acidophilusin neonatal gnotobiotic piglets

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