Transcriptional Regulation of Inflammasomes Cornut, Maxence; Bourdonnay, Emilie; Henry, Thomas
International journal of molecular sciences,
10/2020, Letnik:
21, Številka:
21
Journal Article
Recenzirano
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Inflammasomes are multimolecular complexes with potent inflammatory activity. As such, their activity is tightly regulated at the transcriptional and post-transcriptional levels. In this review, we ...present the transcriptional regulation of inflammasome genes from sensors (e.g., NLRP3) to substrates (e.g., IL-1β). Lineage-determining transcription factors shape inflammasome responses in different cell types with profound consequences on the responsiveness to inflammasome-activating stimuli. Pro-inflammatory signals (sterile or microbial) have a key transcriptional impact on inflammasome genes, which is largely mediated by NF-κB and that translates into higher antimicrobial immune responses. Furthermore, diverse intrinsic (e.g., circadian clock, metabolites) or extrinsic (e.g., xenobiotics) signals are integrated by signal-dependent transcription factors and chromatin structure changes to modulate transcriptionally inflammasome responses. Finally, anti-inflammatory signals (e.g., IL-10) counterbalance inflammasome genes induction to limit deleterious inflammation. Transcriptional regulations thus appear as the first line of inflammasome regulation to raise the defense level in front of stress and infections but also to limit excessive or chronic inflammation.
JAK-STAT signaling mediates the actions of numerous cytokines and growth factors, and its endogenous brake is the family of SOCS proteins. Consistent with their intracellular roles, SOCS proteins ...have never been identified in the extracellular space. Here we report that alveolar macrophages can secrete SOCS1 and -3 in exosomes and microparticles, respectively, for uptake by alveolar epithelial cells and subsequent inhibition of STAT activation. Secretion is tunable and occurs both in vitro and in vivo. SOCS secretion into lung lining fluid was diminished by cigarette smoking in humans and mice. Secretion and transcellular delivery of vesicular SOCS proteins thus represent a new model for the control of inflammatory signaling, which is subject to dysregulation during states of inflammation.
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•The different GSDM genes have specific tissue expression patterns.•GSDM expression is modulated by environmental factors, cell stress and cytokines.•SNPs impact GSDM expression and ...susceptibility to asthma and IBD.•GSDM expression levels control the balance between apoptosis and pyroptosis.•Silencing of GSDM impacts tumor immunosurveillance and response to therapy.•Targeting epigenetic modifications is a promising therapeutic avenue.
Gasdermins (GSDM) are a family of six homologous proteins (GSDMA to E and Pejvakin) in humans. GSDMA-E are pore-forming proteins targeting the plasma membrane to trigger a rapid cell death termed pyroptosis or bacterial membranes to promote antibacterial immune defenses. Activation of GSDM relies on a proteolytic cleavage but is highly dependent on GSDM expression levels. The different GSDM genes have tissue-specific expression pattern although metabolic, environmental signals, cell stress and numerous cytokines modulate their expression levels in tissues. Furthermore, expression of GSDM genes can be modulated by polymorphisms and have been associated with susceptibility to asthma, inflammatory bowel diseases and rhinovirus wheezing illness. Finally, the expression level of GSDMs controls the balance between apoptosis and pyroptosis affecting both the response and the toxicity to chemotactic drugs and antitumoral treatments. Numerous cancer demonstrate positive or negative modulation of GSDM expression levels correlating with distinct tumor-specific prognosis. In this review, we present the transcriptional and epigenetic mechanisms controlling GSDM levels and their functional consequences in asthma, infection, cancers and inflammatory bowel disease to highlight how this first layer of regulations has key consequences on disease susceptibility and response to treatment.
Chronic exposure to inorganic arsenic, a widely distributed environmental contaminant, can lead to toxic effects, including immunosuppression. Owing to the established roles of human macrophages in ...immune defense, we determined, in the present study, whether inorganic arsenic can affect these major immune cells. Our results demonstrate that noncytotoxic concentrations of arsenic trioxide (As2O3), an inorganic trivalent form, markedly impair differentiated features of human blood monocyte-derived macrophages. First, treatment of macrophages with 1 microM As2O3 induced a rapid cell rounding and a subsequent loss of adhesion. These morphologic alterations were associated with a marked reorganization of actin cytoskeleton, which includes retraction of peripheral actin extensions and formation of a cortical actin ring. In addition, As2O3 reduced expression of various macrophagic surface markers, enhanced that of the monocytic marker CD14, and altered both endocytosis and phagocytosis; unexpectedly, exposure of macrophages to the metalloid also strongly potentiated expression of TNFalpha and IL-8 induced by LPS. Finally, like monocytes, As2O3-treated macrophages can be differentiated into dendritic-like cells. Impairment of macrophage function by As2O3 mainly resulted from activation of a RhoA/Rho-associated kinase pathway; indeed, pretreatment of macrophages with the Rho-associated kinase inhibitor Y-27632 prevented metalloid effects on cytoskeleton and phagocytosis. Moreover, As2O3 was found to increase level of the active GTP-bound form of RhoA and that of phosphorylated-Moesin, a major cytoskeleton adaptor protein involved in RhoA regulation. Taken together, our results demonstrated that human macrophages constitute sensitive targets of inorganic arsenic, which may contribute to immunotoxicity of this environmental contaminant.
Background Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E2 or of specific E prostanoid (EP) ...receptors is not known. Objective Here we tested the role of EP2 signaling in allergic asthma. Methods Wild-type (WT) and EP2−/− mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE2 analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2−/− CD4 T cells was used to validate the importance of EP2 expression on T cells. Results Compared with WT mice, EP2−/− mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2−/− mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2−/− mice, subcutaneous administration of misoprostol during sensitization inhibited allergic inflammation. PGE2 decreased cytokine production and inhibited signal transducer and activator of transcription 6 phosphorylation by CD3/CD28-stimulated CD4+ T cells. Coculture of flow cytometry–sorted splenic CD4+ T cells and CD11c+ dendritic cells from WT or EP2−/− mice suggested that the increased IL-13 production in EP2−/− mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4+ EP2−/− T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4+ T cells. Conclusion We conclude that the PGE2 -EP2 axis is an important endogenous brake on allergic airway inflammation and primarily targets T cells and that its agonism represents a potential novel therapeutic approach to asthma.
Macrophage ingestion of the yeast Candida albicans requires its recognition by multiple receptors and the activation of diverse signaling programs. Synthesis of the lipid mediator prostaglandin E(2) ...(PGE(2)) and generation of cyclic adenosine monophosphate (cAMP) also accompany this process. Here, we characterized the mechanisms underlying PGE(2)-mediated inhibition of phagocytosis and filamentous actin (F-actin) polymerization in response to ingestion of C. albicans by alveolar macrophages. PGE(2) suppressed phagocytosis and F-actin formation through the PGE(2) receptors EP2 and EP4, cAMP, and activation of types I and II protein kinase A. Dephosphorylation and activation of the actin depolymerizing factor cofilin-1 were necessary for these inhibitory effects of PGE(2). PGE(2)-dependent activation of cofilin-1 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated. Because enhanced production of PGE(2) accompanies many immunosuppressed states, the PTEN-dependent pathway described here may contribute to impaired antifungal defenses.
In lung macrophages, inhibition of p40phox by PGE2 represents a brake on bacterial killing, and likely contributes to impaired lung innate immunity.
PGE2, produced in the lung during infection with ...microbes such as Klebsiella pneumoniae, inhibits alveolar macrophage (AM) antimicrobial functions by preventing H2O2 production by NADPH oxidase (NADPHox). Activation of the NADPHox complex is poorly understood in AMs, although in neutrophils it is known to be mediated by kinases including PI3K/Akt, protein kinase C (PKC) δ, p21‐activated protein kinase (PAK), casein kinase 2 (CK2), and MAPKs. The p40phox cytosolic subunit of NADPHox has been recently recognized to function as a carrier protein for other subunits and a positive regulator of oxidase activation, a role previously considered unique to another subunit, p47phox. The regulation of p40phox remains poorly understood, and the effect of PGE2 on its activation is completely undefined. We addressed these issues in rat AMs activated with IgG‐opsonized K. pneumoniae. The kinetics of kinase activation and the consequences of kinase inhibition and silencing revealed a critical role for a PKCδ‐PAK‐class I PI3K/Akt1 cascade in the regulation of p40phox activation upon bacterial challenge in AMs; PKCα, ERK, and CK2 were not involved. PGE2 inhibited the activation of p40phox, and its effects were mediated by protein kinase A type II, were independent of interactions with anchoring proteins, and were directed at the distal class I PI3K/Akt1 activation step. Defining the kinases that control AM p40phox activation and that are the targets for inhibition by PGE2 provides new insights into immunoregulation in the infected lung.
Problem
Clostridium sordellii causes endometrial infections, but little is known regarding host defenses against this pathogen.
Method of study
We tested the hypothesis that the immunoregulatory ...lipid prostaglandin (PG) E2 suppresses human macrophage clearance of C. sordellii through receptor‐induced increases in intracellular cyclic adenosine monophosphate (cAMP). The THP‐1 macrophage cell line was used to quantify C. sordellii phagocytosis.
Results
PGE2 increased cAMP levels, activated protein kinase A (PKA), and inhibited the class A scavenger receptor‐dependent phagocytosis of C. sordellii. Activation of the EP2 and EP4 receptors increased intracellular cAMP and inhibited phagocytosis, with evidence favoring a more important role for EP4 over EP2. This was supported by EP receptor expression data and the use of pharmacological receptor antagonists. In addition, the PKA isoform RI appeared to be more important than RII in mediating the suppression of ingestion of C. sordellii.
Conclusion
The endogenous lipid mediator PGE2 impairs human innate immune responses against C. sordellii.
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