Dataset Information

ATF3 Stimulates IL-17A by Regulating Intracellular Ca²⁺/ROS-Dependent IL-1? Activation During Streptococcus pneumoniae Infection.

ABSTRACT: Activating transcription factor-3 (ATF3) in the ER stress pathway induces cytokine production and promotes survival during gram-positive bacterial infection. IL-17A is a critical cytokine that is essential for clearance of Streptococcus pneumoniae. However, the mechanism by which ATF3 induces IL-17A production remains unknown. Here, we show that ATF3 induces IL-17A production via NLRP3 inflammasome-dependent IL-1? secretion. Survival rates were comparable in IL-17A-depleted and ATF3 KO mice but were lower than in WT mice treated with isotype control, indicating that ATF3 positively regulated IL-17A production. Indeed, ATF3 KO mice showed a marked reduction in IL-17A protein and mRNA expression compared to levels in WT mice. Moreover, mitochondrial IL-1? production by bone marrow-derived macrophages was significantly reduced in ATF3 KO mice as a result of the disruption of cellular ROS and Ca²⁺ homeostasis. Accordingly, ATF3 KO mice displayed diminished survival and bacterial clearance following S. pneumoniae infection. Taken together, these data suggest a mechanism in which macrophage ATF3 promotes IL-17A production in ?? T cells to rapidly induce host defenses during early S. pneumoniae infection.

SUBMITTER: Lee S

PROVIDER: S-EPMC6125349 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

ATF3 Stimulates IL-17A by Regulating Intracellular Ca2+/ROS-Dependent IL-1β Activation During Streptococcus pneumoniae Infection.

Lee Seungyeop S Kim Gyu-Lee GL Kim Na Young NY Kim Se-Jin SJ Ghosh Prachetash P Rhee Dong-Kwon DK

Frontiers in immunology 20180830

Activating transcription factor-3 (ATF3) in the ER stress pathway induces cytokine production and promotes survival during gram-positive bacterial infection. IL-17A is a critical cytokine that is essential for clearance of Streptococcus pneumoniae. However, the mechanism by which ATF3 induces IL-17A production remains unknown. Here, we show that ATF3 induces IL-17A production via NLRP3 inflammasome-dependent IL-1β secretion. Survival rates were comparable in IL-17A-depleted and ATF3 KO mi ...[more]

PMID: 30214444

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Project description:Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+-dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM-causing variants of human troponin-T, troponin-I, and α-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ∼50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant decrease in basal sarcomere length and slowed relaxation. HCM mutant cells had higher sodium/calcium exchanger activity, sarcoplasmic reticulum Ca2+ load, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity driven by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of phospholamban. The ryanodine receptor (RyR) leak/load relationship was also increased, driven by CaMKII-mediated RyR phosphorylation. Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal-regulated kinase pathways. Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM.

Dataset Information

ATF3 Stimulates IL-17A by Regulating Intracellular Ca²⁺/ROS-Dependent IL-1? Activation During Streptococcus pneumoniae Infection.

Publications

ATF3 Stimulates IL-17A by Regulating Intracellular Ca<sup>2+</sup>/ROS-Dependent IL-1β Activation During <i>Streptococcus pneumoniae</i> Infection.

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Dataset Information

ATF3 Stimulates IL-17A by Regulating Intracellular Ca2+/ROS-Dependent IL-1? Activation During Streptococcus pneumoniae Infection.

Publications

ATF3 Stimulates IL-17A by Regulating Intracellular Ca<sup>2+</sup>/ROS-Dependent IL-1β Activation During <i>Streptococcus pneumoniae</i> Infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

ATF3 Stimulates IL-17A by Regulating Intracellular Ca²⁺/ROS-Dependent IL-1? Activation During Streptococcus pneumoniae Infection.