Adenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway

Ouyang, Xinshou; Ghani, Ayaz; Malik, Ahsan; Wilder, Tuere; Colegio, Oscar R.; Flavell, Richard A.; Cronstein, Bruce N.; Mehal, Wajahat Z.

doi:10.1038/ncomms3909

Cited by 103 publications

(99 citation statements)

References 32 publications

(46 reference statements)

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“…This low cytoplasmic Ca 2ϩ concentration in IL-10 Ϫ/Ϫ DCs might be mediated by the inhibited P2X7 receptor. Intracellular cAMP regulates the NLRP3 inflammasome; studies show that cAMP suppresses NLRP3 inflammasome activation through the inhibition of inflammasome assembly (24,39). Our results showed an inverse correlation between the levels of cAMP and the presence or absence of IL-10, suggesting that Chlamydia-pulsed IL-10 Ϫ/Ϫ DCs had increased levels of cAMP synthesis, which might repress NLRP3 inflammasome formation.…”

Section: Discussionsupporting

confidence: 58%

Interleukin-10 Modulates Antigen Presentation by Dendritic Cells through Regulation of NLRP3 Inflammasome Assembly during Chlamydia Infection

et al. 2015

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e Interleukin-10 (IL-10) has been implicated in susceptibility to genital chlamydial infection and the development of tubal pathologies. IL-10 limitation also resulted in the rapid elicitation of immune responses against Chlamydia, and decreased levels of IL-10 correlated with protective anti-Chlamydia immunity. To investigate the molecular basis for these effects, we compared the reproductive pathologies and fertility rates in Chlamydia-infected wild-type (WT) and IL-10-knockout (IL-10 ؊/؊ ) mice; we also analyzed the expression of the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily, IL-1␤ production, NLRP3 inflammasome assembly and activation, and the immunostimulatory capacity and apoptotic predilection of Chlamydia-exposed dendritic cells (DCs) from WT and IL-10 ؊/؊ mice. Our results revealed that, in addition to the rapid clearance of infection, genitally infected IL-10 ؊/؊ mice were protected from tubal pathologies and infertility, whereas WT (IL-10 ؉/؉ ) mice were not. Chlamydia-pulsed IL-10 ؊/؊ DCs expressed larger numbers of TLR4/IL-1R molecules and had enhanced IL-1␤ production. In addition, NLRP3 inflammasome assembly was suppressed in IL-10 ؊/؊ DCs through the inhibition of the P2X purinoceptor 7 (P2X7) receptor (P2X7R), an ATP-gated ion channel, and a decrease in intracellular Ca 2؉ levels, which inhibited DC apoptosis. Thus, the potent immunostimulatory capacity of IL-10-deficient DCs is due, at least in part, to the suppression of the intracellular inflammasome assembly, which prevents DC apoptosis, allowing efficient antigen presentation. The results indicate that IL-10 deficiency enables efficient antigen presentation by DCs for rapid and enhanced immune activation against Chlamydia, which results in rapid microbial clearance, which prevents tubal pathologies during infection. Our finding has important implications for the induction of protective immunity against Chlamydia and other infectious and noninfectious diseases by vaccines.

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Section: Discussionsupporting

confidence: 58%

Interleukin-10 Modulates Antigen Presentation by Dendritic Cells through Regulation of NLRP3 Inflammasome Assembly during Chlamydia Infection

et al. 2015

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“…4C), affecting subsequent PGN/NOD2 interaction, which may impair IL-1b secretion. However, in contrast, others showed that adenosine signaling was required to induce IL-1b secretion through the A2aR (45,49). Thus, it would be interesting to investigate the role of adenosine produced by S. aureus on IL-1b secretion.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus Adenosine Inhibits sPLA2-IIA–Mediated Host Killing in the Airways

Pernet

Brunet

Guillemot

et al. 2015

The Journal of Immunology

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Staphylococcus aureus is a common cause of bacterial infections in respiratory diseases. It secretes molecules to dampen host immunity, and the recently identified adenosine is one of these molecules. The type IIA secretory phospholipase A2 (sPLA2-IIA) is a host protein endowed with antibacterial properties, especially against Gram-positive bacteria such as S. aureus. However, the role of adenosine in sPLA2-IIA–mediated S. aureus killing by host is still unknown. The present studies showed that the S. aureus mutant lacking adenosine production (∆adsA strain) increased sPLA2-IIA expression in guinea pig airways and was cleared more efficiently, compared with the wild-type strain. S. aureus ∆adsA strain induced sPLA2-IIA expression by alveolar macrophages after phagocytic process via NOD2–NF-κB–dependent mechanism. However, S. aureus adenosine (wild-type and adsA-complemented strains) and exogenous adenosine downregulated S. aureus phagocytosis by alveolar macrophages, leading to inhibition of sPLA2-IIA expression. This occurred through inhibition of p38 phosphorylation via adenosine receptors A2a-, A2b-, and protein kinase A–dependent pathways. Taken together, our studies suggest that, in the airway, S. aureus escapes sPLA2-IIA–mediated killing through adenosine-mediated inhibition of phagocytosis and sPLA2-IIA expression.

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“…NPCs contained liver endothelial, stellate, and Kupffer cells; all were maintained in DMEM containing 10% FBS. Mouse macrophages were isolated and maintained as previously described (36). Mouse primary cholangiocytes were provided by Carlo Spirli (Yale University) as previously described (37).…”

Section: Methodsmentioning

confidence: 99%

Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response

et al. 2017

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Adenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway

Cited by 103 publications

References 32 publications

Interleukin-10 Modulates Antigen Presentation by Dendritic Cells through Regulation of NLRP3 Inflammasome Assembly during Chlamydia Infection

Interleukin-10 Modulates Antigen Presentation by Dendritic Cells through Regulation of NLRP3 Inflammasome Assembly during Chlamydia Infection

Staphylococcus aureus Adenosine Inhibits sPLA2-IIA–Mediated Host Killing in the Airways

Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response

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