scholarly journals Type 1 interferon-dependent repression of NLRC4 and iPLA2 licenses down-regulation ofSalmonellaflagellin inside macrophages

2020 ◽  
Vol 117 (47) ◽  
pp. 29811-29822
Author(s):  
Ajay Suresh Akhade ◽  
Shaikh M. Atif ◽  
Bhavana S. Lakshmi ◽  
Neha Dikshit ◽  
Kelly T. Hughes ◽  
...  
Keyword(s):  
Cell Death ◽  
Cross Talk ◽  
Biosynthetic Enzyme ◽  
Regulatory Effect ◽  
Tlr Signaling ◽  
Down Regulation ◽  
Sensing Mechanism ◽  
Host Cues

Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but little is known about whether this innate sensing mechanism has any regulatory effect on the expression of stimulatory ligands by the pathogen. During infection withSalmonellaand many other pathogens, flagellin is a major activator of NLRC4 inflammasome-mediated macrophage pyroptosis and pathogen eradication.Salmonellaswitches to a flagellin-low phenotype as infection progresses to avoid this mechanism of clearance by the host. However, the host cues thatSalmonellaperceives to undergo this switch remain unclear. Here, we report an unexpected role of the NLRC4 inflammasome in promoting expression of its microbial ligand, flagellin, and identify a role for type 1 IFN signaling in switching ofSalmonellato a flagellin-low phenotype. Early in infection, activation of NLRC4 by flagellin initiates pyroptosis and concomitant release of lysophospholipids which in turn enhance expression of flagellin bySalmonellathereby amplifying its ability to elicit cell death. TRIF-dependent production of type 1 IFN, however, later represses NLRC4 and the lysophospholipid biosynthetic enzyme iPLA2, causing a decline in intracellular lysophospholipids that results in down-regulation of flagellin expression bySalmonella. These findings reveal a previously unrecognized immune-modulating regulatory cross-talk between endosomal TLR signaling and cytosolic NLR activation with significant implications for the establishment of infection withSalmonella.

scholarly journals Restoration of Defective Cross Talk in ssi2 Mutants: Role of Salicylic Acid, Jasmonic Acid, and Fatty Acids in SSI2-Mediated Signaling

2003 ◽  
Vol 16 (11) ◽  
pp. 1022-1029 ◽  
Author(s):  
Pradeep Kachroo ◽  
Aardra Kachroo ◽  
Ludmila Lapchyk ◽  
David Hildebrand ◽  
Daniel F. Klessig
Keyword(s):  
Cell Death ◽  
Salicylic Acid ◽  
Jasmonic Acid ◽  
Cross Talk ◽  
Pr Genes ◽  
Exogenous Application ◽  
Basal Level Expression ◽  
Sa Signaling ◽  
Spontaneous Cell Death

The Arabidopsis mutants ssi2 and fab2 are defective in stearoyl ACP desaturase, which causes altered salicylic acid (SA)- and jasmonic acid (JA)-mediated defense signaling. Both ssi2 and fab2 plants show spontaneous cell death, express PR genes constitutively, accumulate high levels of SA, and exhibit enhanced resistance to bacterial and oomycete pathogens. In contrast to constitutive activation of the SA pathway, ssi2 and fab2 plants are repressed in JA-mediated induction of the PDF1.2 gene, which suggests that the SSI2-mediated signaling pathway modulates cross talk between the SA and JA pathways. In this study, we have characterized two recessive nonallelic mutants in the ssi2 background, designated as rdc (restorer of defective cross talk) 2 and rdc8. Both ssi2 rdc mutants are suppressed in constitutive SA signaling, show basal level expression of PR-1 gene, and induce high levels of PDF1.2 in response to exogenous application of JA. Interestingly, while the rdc8 mutation completely abolishes spontaneous cell death in ssi2 rdc8 plants, the ssi2 rdc2 plants continue to show some albeit reduced cell death. Fatty acid (FA) analysis showed a reduction in 16:3 levels in ssi2 rdc8 plants, which suggests that this mutation may limit the flux of FAs into the pro-karyotic pathway of glycerolipid biosynthesis. Both rdc2 and rdc8 continue to accumulate high levels of 18:0, which suggests that 18:0 levels were responsible for neither constitutive SA signaling nor repression of JA-induced expression of the PDF1.2 gene in ssi2 plants. We also analyzed SA and JA responses of the fab2-derived shs1 mutant, which accumulates levels of 18:0 over 50% lower than those in the fab2 plants. Even though fab2 shs1 plants were morphologically bigger than fab2 plants, they expressed PR genes constitutively, showed HR-like cell death, and accumulated elevated levels of SA. However, unlike the ssi2 rdc plants, fab2 shs1 plants were unable to induce high levels of PDF1.2 expression in response to exogenous application of JA. Together, these results show that defective cross talk in ssi2 can be restored by second site mutations and is independent of morphological size of the plants, cell death, and elevated levels of 18:0.

Abstract 26: Fibroblast Growth Factor 21 Prevents Diabetic Cardiomyopathy by Attenuating Cardiac Lipotoxicity via Erk1/2-dependent Signaling Pathway in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yi Tan ◽  
Chi Zhang ◽  
Xiaoqing Yan ◽  
Zhifeng Huang ◽  
Junlian Gu ◽  
...  
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Cell ◽  
Diabetic Mice ◽  
Ampk Signaling

The role of FGF21 plays in the development and progression of diabetic cardiomyopathy (DCM) has not been addressed. Here we demonstrated that type 1 diabetes decreased FGF21 levels in the blood, but up-regulated cardiac fgf21 expression about 40 fold at 2 months and 3-1.5 fold at 4 and 6 months after diabetes, which indicated a cardiac specific FGF21 adaptive up-regulation. To define the critical role of FGF21 in DCM, type 1 diabetes was induced in FGF21 knock out (FGF21KO) mice. At 1, 2 and 4 months after diabetes onset, no significant differences between FGF21KO and wild type (WT) diabetic mice in blood glucose and triglyceride levels were observed. But FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodeling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Mechanistically, FGF21 reduced palmitate-induced cardiac cell death, which was accompanied by up-regulation of cardiac Erk1/2, p38 MAPK and AMPK phosphorylation. Inhibition of each kinase with its inhibitor and/ or siRNA revealed that FGF21 prevents palmitate-induced cardiac cell death via up-regulating the Erk1/2-dependent p38 MAPK/AMPK signaling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic mice significantly prevented cardiac cell death and reduced inactivation of Erk1/2, p38 MAPK and AMPK, and prevented cardiac remodeling and dysfunction at late-stage. Our results demonstrate that cardiac FGF21 decompensation may contribute to the development of DCM and FGF21 may be a therapeutic target for the treatment of diabetic cardiac damage via activation of Erk1/2-P38 MAPK-AMPK signaling.

scholarly journals Overexpression of CuZn superoxide dismutase protects RAW 264.7 macrophages against nitric oxide cytotoxicity

1999 ◽  
Vol 338 (2) ◽  
pp. 295-303 ◽  
Author(s):  
Florian BROCKHAUS ◽  
Bernhard BRÜNE
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Superoxide Dismutase ◽  
Uric Acid ◽  
No Synthase ◽  
Raw 264.7 ◽  
Down Regulation ◽  
Raw 264.7 Macrophages ◽  
Inducible No Synthase

Initiation of nitric oxide (NO•)-mediated apoptotic cell death in RAW 264.7 macrophages is associated with up-regulation of mitochondrial manganese superoxide dismutase (MnSOD; SOD2) and down-regulation of cytosolic copper zinc superoxide dismutase (CuZnSOD; SOD1) at their individual mRNA and protein levels. To evaluate the decreased CuZnSOD expression and the initiation of apoptosis we stably transfected macrophages to overexpress human CuZnSOD. Individual clones revealed a 2-fold increase in CuZnSOD activity. Expression of a functional and thus protective CuZnSOD was verified by attenuated superoxide (O2•-)-mediated apoptotic as well as necrotic cell death. In this study we showed that SOD-overexpressing macrophages (R-SOD1-12) were also protected against NO•-initiated programmed cell death. Protection was substantial towards NO• derived from exogenously added NO donors or when NO• was generated by inducible NO synthase activation, and was evident at the level of p53 accumulation, caspase activation and DNA fragmentation. Stimulation of parent and SOD-overexpressing cells with a combination of lipopolysaccharide and murine interferon γ produced equivalent amounts of nitrite/nitrate, which ruled out attenuated inducible NO• synthase activity during protection. Because protection by a O2•--scavenging system during NO•-intoxication implies a role of NO• and O2•- in the progression of cell damage, we used uric acid to delineate the role of peroxynitrite during NO•-elicited apoptosis. The peroxynitrite scavenger uric acid left S-nitrosoglutathione or spermine-NO-elicited apoptosis unaltered, blocking only 3-morpholinosydnonimine-mediated cell death. As a result we exclude peroxynitrite from contributing, to any major extent, to NO•-mediated apoptosis. Therefore protection observed with CuZnSOD overexpression is unlikely to stem from interference with peroxynitrite formation and/or action. Unequivocally, the down-regulation of CuZnSOD is associated with NO• cytotoxicity, whereas CuZnSOD overexpression protects macrophages from apoptosis.

The role of basophil via TLR signaling in patients with type 1 autoimmune pancreatitis

Pancreatology ◽  
2016 ◽  
Vol 16 (4) ◽  
pp. S40
Author(s):  
Masato Yanagawa ◽  
Kazushige Uchida ◽  
Manami Ikemune ◽  
Tsukasa Ikeura ◽  
Masaaki Shimatani ◽  
...  
Keyword(s):  
Autoimmune Pancreatitis ◽  
Tlr Signaling ◽  
Type 1 Autoimmune Pancreatitis

scholarly journals SIRT1 Promotes Cell Survival under Stress by Deacetylation-Dependent Deactivation of Poly(ADP-Ribose) Polymerase 1

2009 ◽  
Vol 29 (15) ◽  
pp. 4116-4129 ◽  
Author(s):  
Senthilkumar B. Rajamohan ◽  
Vinodkumar B. Pillai ◽  
Madhu Gupta ◽  
Nagalingam R. Sundaresan ◽  
Konstantin G. Birukov ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cell Survival ◽  
Cross Talk ◽  
Gene Promoter ◽  
Stress Conditions ◽  
Transcriptional Level ◽  
A Cell

ABSTRACT Poly(ADP-ribose) polymerase 1 (PARP1) and SIRT1 deacetylase are two NAD-dependent enzymes which play major roles in the decision of a cell to live or to die in a stress situation. Because of the dependence of both enzymes on NAD, cross talk between them has been suggested. Here, we show that PARP1 is acetylated after stress of cardiomyocytes, resulting in the activation of PARP1, which is independent of DNA damage. SIRT1 physically binds to and deacetylates PARP1. Increased acetylation of PARP1 was also detected in hearts of SIRT1−/− mice, compared to that detected in the hearts of SIRT1+/+ mice, confirming a role of SIRT1 in regulating the PARP1 acetylation in vivo. SIRT1-dependent deacetylation blocks PARP1 activity, and it protects cells from PARP1-mediated cell death. We also show that SIRT1 negatively regulates the activity of the PARP1 gene promoter, thus suggesting that the deacetylase controls the PARP1 activity at the transcriptional level as well. These data demonstrate that the activity of PARP1 is under the control of SIRT1, which is necessary for survival of cells under stress conditions.

scholarly journals The human programmed cell death-2 (PDCD2) gene is a target of BCL6 repression: Implications for a role of BCL6 in the down-regulation of apoptosis

2002 ◽  
Vol 99 (5) ◽  
pp. 2860-2865 ◽  
Author(s):  
B. W. Baron ◽  
J. Anastasi ◽  
M. J. Thirman ◽  
Y. Furukawa ◽  
S. Fears ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Down Regulation

scholarly journals Modulation of Cellular Protein Trafficking by Human Immunodeficiency Virus Type 1 Nef: Role of the Acidic Residue in the ExxxLL Motif

2006 ◽  
Vol 80 (4) ◽  
pp. 1837-1849 ◽  
Author(s):  
Scott H. Coleman ◽  
Ricardo Madrid ◽  
Nanette Van Damme ◽  
Richard S. Mitchell ◽  
Jerome Bouchet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Adaptor Protein ◽  
Cellular Proteins ◽  
Invariant Chain ◽  
Down Regulation ◽  
Immunodeficiency Virus

ABSTRACT The nef gene contributes to the replication of primate lentiviruses by altering the trafficking of cellular proteins involved in adaptive immunity (class I and II major histocompatibility complex [MHC]) and viral transmission (CD4 and DC-SIGN). A conserved acidic leucine-based sequence (E160xxxLL) within human immunodeficiency virus type 1 (HIV-1) Nef binds to the cellular adaptor protein (AP) complexes, which mediate protein sorting into endosomal vesicles. The leucine residues in this motif are required for the down-regulation of CD4 and for the up-regulation of DC-SIGN and the invariant chain of MHC class II, but the role of the acidic residue is unclear. Here, substitution of E160 with uncharged residues impaired the ability of Nef to up-regulate the expression of the invariant chain and DC-SIGN at the cell surface, whereas substitution with a basic residue was required for a similar effect on the down-regulation of CD4. All substitutions of E160 relieved the Nef-mediated block to transferrin uptake. E160 was required for the efficient interaction of Nef with AP-1 and AP-3 and for the stabilization of these complexes on endosomal membranes in living cells. Systematic mutation of the ExxxLL sequence together with correlation of binding and functional data leads to the hypotheses that AP-1 and AP-3 are major cofactors for the effect of Nef on the trafficking of transferrin, are less important but contribute to the modulation of the invariant chain and DC-SIGN, and are least critical for the modulation of CD4. The data suggest that the E160 residue plays a differential role in the modulation of leucine-dependent Nef-targets and support a model in which distinct AP complexes are used by Nef to modulate different cellular proteins.

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