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.m111.275370

Cited by 220 publications

(160 citation statements)

References 62 publications

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“…Glucocorticoids have also been shown to induce the expression of NOD-like receptor family, pyrin domain containing 3 gene (NLRP3), a central component of the inflammasome, in both cultured and primary macrophages (Figure 5B) [77]. Glucocorticoid induction of NLRP3 sensitized macrophages to extracellular ATP which resulted in the secretion of pro-inflammatory cytokines, IL1b, TNF-α, and IL-6 [77].…”

Section: Pro-inflammatory Effects Of Glucocorticoidsmentioning

confidence: 99%

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One Hormone, Two Actions: Anti- and Pro-Inflammatory Effects of Glucocorticoids

Cruz‐Topete¹,

Cidlowski²

2014

Neuroimmunomodulation

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378

294

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Glucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress. Since their discovery in the 1940s, glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers. In the traditional view, glucocorticoids are regarded as anti-inflammatory molecules; however, emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated. The anti-inflammatory activity of glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their steroid receptor, the glucocorticoid receptor (GR). The mechanisms modulating the pro-inflammatory effects of glucocorticoids are not well understood. In this review, we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune response. We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor (pro-inflammatory effects) and subsequently restore homeostasis (anti-inflammatory effects). Finally, we propose that determining the mechanisms which underlie the tissue-specific effects of glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies.

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Section: Pro-inflammatory Effects Of Glucocorticoidsmentioning

confidence: 99%

“…Glucocorticoid induction of NLRP3 sensitized macrophages to extracellular ATP which resulted in the secretion of pro-inflammatory cytokines, IL1b, TNF-α, and IL-6 [77]. In addition, glucocorticoids have been reported to induce the expression of the purinergic receptor P2Y2R (Figure 5C).…”

Section: Pro-inflammatory Effects Of Glucocorticoidsmentioning

confidence: 99%

One Hormone, Two Actions: Anti- and Pro-Inflammatory Effects of Glucocorticoids

Cruz‐Topete¹,

Cidlowski²

2014

Neuroimmunomodulation

Self Cite

378

294

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“…These sequelae are proposed to relate to the chronic inflammation that occurs despite antiretroviral therapy. In recent years, extracellular ATP (eATP) has been recognized as a signaling molecule important in chronic inflammation that signals through purinergic receptors on the cell membrane (5)(6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

Swartz

Esposito

Durham

et al. 2014

J Virol

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Human immunodeficiency virus type 1 (HIV-1) infection is chronic and presently still incurable. Antiretroviral drugs effectively suppress replication; however, persistent activation of inflammatory pathways remains a key cause of morbidity. Recent studies proposed that purinergic signaling is required for HIV-1 infection. Purinergic receptors are distributed throughout a wide variety of tissue types and detect extracellular ATP as a danger signal released from dying cells. We have explored how these pathways are involved in the transmission of HIV-1 from cell to cell through virological synapses. Infection of CD4 ؉ T lymphocytes with HIV-1 in the presence of an inhibitor of P2X receptors effectively inhibited HIV-1 infection through both cell-free and cellto-cell contact in a dose-dependent manner. Inhibition of direct cell-to-cell infection did not affect the formation of virological synapses or the subsequent cell-to-cell transfer of HIV-1. During both cell-free and cell-to-cell CD4 ؉ T lymphocyte infection, purinergic antagonists blocked infection at the level of viral membrane fusion. During cell-to-cell transmission, we observed CXCR4 colocalization with the newly internalized virus particles within target lymphocytes and found that the purinergic antagonists did not impair the recruitment of the coreceptor CXCR4 to the site of Gag internalization in the target cell. In a screen of a library of purinergic antagonists, we found that the most potent inhibitors of HIV-1 fusion were those that target P2X receptors, while P2Y-selective receptor antagonists or adenosine receptor antagonists were ineffective. Our results suggest that P2X receptors may provide a therapeutic target and that purinergic antagonists may have potent activity against viral infection of CD4 ؉ T lymphocytes by both cell-free and cell-to-cell transmission. IMPORTANCEThis study identifies purinergic antagonists to be potent inhibitors of HIV-1 cell-free and cell-to-cell-mediated infection and provides a stepwise determination of when these compounds inhibit HIV-1 infection. These data provide a rationale for the development of novel antiretroviral therapies that have a dual role in both direct antiviral activity and the reduction of HIV-associated inflammation. Purinergic antagonists are shown here to have equivalent efficacy in inhibiting HIV infection via cell-free and cell-to-cell infection, and it is shown that purinergic receptors could provide an attractive therapeutic anti-HIV target that might avoid resistance by targeting a host signaling pathway that potently regulates HIV infection. The high-throughput screen of HIV-1 fusion inhibitors further defines P2X-selective compounds among the purinergic compounds as being the most potent HIV entry inhibitors. Clinical studies on these drugs for other inflammatory indications suggest that they are safe, and thus, if developed for use as anti-HIV agents, they could reduce both HIV replication and HIV-related inflammation.

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“…20,21,74 The effects described in this study are timely, and have a potential impact on GBM treatment, given the recent development of several immunotherapy approaches predicated on activation of innate immune cell functions, including macrophages that reside within the tumor microenvironment. As a result of the transient nature and reversibility of steroid mediated immune suppression, as well as the plasticity of macrophages found in the tumor microenvironment, patients on steroids are likely good candidates for immunotherapy approaches if weaning below immunomodulatory doses are included in the clinical protocols to restore the antigen presentation and immune activating functions of monocytes and macrophages in patients with gliomas.…”

Section: Discussionmentioning

confidence: 94%

“…20-22 A recent study evaluating grades II-IV astrocytomas demonstrates that CD163 mRNA expression increases with increasing grade of astrocytoma, and that CD163+ cells produce IL-10 in the GBM tumor microenvironment. 23 Furthermore, this report suggests that CD163 could be used as a prognostic indicator for grade III astroctyomas.…”

Section: Resultsmentioning

confidence: 99%

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

et al. 2018

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Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue.Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

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Glucocorticoids Sensitize the Innate Immune System through Regulation of the NLRP3 Inflammasome

Cited by 220 publications

References 62 publications

One Hormone, Two Actions: Anti- and Pro-Inflammatory Effects of Glucocorticoids

One Hormone, Two Actions: Anti- and Pro-Inflammatory Effects of Glucocorticoids

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

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