Cross talk of the first-line defense TLRs with PI3K/Akt pathway, in preconditioning therapeutic approach

Pourrajab, Fatemeh; Yazdi, Mohammad Baghi; Zarch, Mojtaba Babaei; Zarch, Mohammadali Babaei; Hekmatimoghaddam, Seyedhossein

doi:10.1186/s40591-015-0041-7

Cited by 46 publications

(48 citation statements)

References 81 publications

(155 reference statements)

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“…Binding of biglycan to TLR2 or TLR4 has been proposed previously in human aortic valve interstitial cells [105] and macrophages [71]. Moreover, TLR ligands have been reported to induce preconditioning-like cardioprotection against SI/R injury [79]. These data suggest that TLR4 signaling plays a MAP kinases [76].…”

Section: Mechanisms Of Cardiocytoprotection Of Biglycan Core Proteinsupporting

confidence: 59%

“…TLR family is expressed not only in immune cells but also on cardiomyocytes, fibroblasts and endothelial cells [79]. Recent evidence suggests that the TLR-mediated immune responses contribute to I/R injury via regulation of cell death and survival [75].…”

Section: Toll-like Receptors and Preconditioning Of The Myocardiummentioning

confidence: 99%

“…Increasing number of studies indicate that various endogenous TLR ligands can act as 'danger-associated molecular patterns' (DAMPs) and can be released upon injury [79][80][81]. The ECM component biglycan was also proposed as a possible ligand for TLR-2/4 receptors in macrophages [71], however, the role of TLR receptors in the cardiac effects of biglycan is unexplored.…”

Section: Toll-like Receptors and Preconditioning Of The Myocardiummentioning

confidence: 99%

“…Several studies suggest that the TLR-2, -4, -9 ligands induce protection against I/R injury, activate the phosphoinositide 3 kinase (PI3K) and Akt signaling that is also involved in ischemic preconditioning, however, the exact molecular mechanism is not known [79].…”

Section: Toll-like Receptors and Preconditioning Of The Myocardiummentioning

confidence: 99%

“…Several studies have shown that activation of RISK pathway -PI3K-Akt or ERK1/2 signaling -protects the heart from I/R injury [73,79]. It has also been shown that there is a crosstalk between the TLR and PI3K-Akt signaling pathways [73].…”

Section: Mechanisms Of Cardiocytoprotection Of Biglycan Core Proteinmentioning

confidence: 99%

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Novel approaches of pharmacological preconditioning: the role of biglycan and miRNAs

Gáspár¹

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Section: Mechanisms Of Cardiocytoprotection Of Biglycan Core Proteinsupporting

confidence: 59%

Section: Toll-like Receptors and Preconditioning Of The Myocardiummentioning

confidence: 99%

Section: Toll-like Receptors and Preconditioning Of The Myocardiummentioning

confidence: 99%

Section: Toll-like Receptors and Preconditioning Of The Myocardiummentioning

confidence: 99%

Section: Mechanisms Of Cardiocytoprotection Of Biglycan Core Proteinmentioning

confidence: 99%

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Novel approaches of pharmacological preconditioning: the role of biglycan and miRNAs

Gáspár¹

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Akt activator SC79 stimulates antibacterial nitric oxide generation in human nasal epithelial cells in vitro

Lee,

Adappa,

Palmer

2024

Int Forum Allergy Rhinol

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BackgroundThe role of Akt in nasal immunity is unstudied. Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) expressed in epithelial ciliated cells. Nitric oxide (NO) production by ciliated cells can have antibacterial and antiviral effects. Increasing nasal NO may be a useful antipathogen strategy in chronic rhinosinusitis (CRS). We previously showed that small‐molecule Akt activator SC79 induces nasal cell NO production and suppresses IL‐8 via the transcription factor Nrf‐2. We hypothesized that SC79 NO production may additionally have antibacterial effects.MethodsNO production was measured using fluorescent dye DAF‐FM. We tested effects of SC79 during co‐culture of Pseudomonas aeruginosa with primary nasal epithelial cells, using CFU counting and live–dead staining to quantify bacterial killing. Pharmacology determined the mechanism of SC79‐induced NO production and tested dependence on Akt.ResultsSC79 induced dose‐dependent, Akt‐dependent NO production in nasal epithelial cells. The NO production required eNOS and Akt. The NO released into the airway surface liquid killed P. aeruginosa. No toxicity (LDH release) or inflammatory effects (IL8 transcription) were observed over 24 h.ConclusionsTogether, these data suggest multiple immune pathways are stimulated by SC79, with antipathogen effects. This in vitro pilot study suggests that a small‐molecule Akt activator may have clinical utility in CRS or respiratory other infection settings, warranting future in vivo studies.

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Cardiolipin activates antigen‐presenting cells via TLR2‐PI3K‐PKN1‐AKT/p38‐NF‐kB signaling to prime antigen‐specific naïve T cells in mice

et al. 2018

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Mitochondrial defects and antimitochondrial cardiolipin (CL) antibodies are frequently detected in autoimmune disease patients. CL from dysregulated mitochondria activates various pattern recognition receptors, such as NLRP3. However, the mechanism by which mitochondrial CL activates APCs as a damage-associated molecular pattern to prime antigen-specific naïve T cells, which is crucial for T-cell-dependent anticardiolipin IgG antibody production in autoimmune diseases is unelucidated. Here, we show that CL increases the expression of costimulatory molecules in CD11c APCs both in vitro and in vivo. CL activates CD11c APCs via TLR2-PI3K-PKN1-AKT/p38MAPK-NF-κB signaling. CD11c APCs that have been activated by CL are sufficient to prime H-Y peptide-specific naïve CD4 T cells and OVA-specific naïve CD8 T cells. TLR2 is necessary for anti-CL IgG antibody responses in vivo. Intraperitoneal injection of CL does not activate CD11c APCs in CD14 KO mice to the same extent as in wild-type mice. CL binds to CD14 (Kd = 7 × 10 M). CD14, but not MD2, plays a role in NF-kB activation by CL, suggesting that CD14 macrophages contribute to recognizing CL. In summary, CL activates signaling pathways in CD11c APCs through a mechanism similar to gram (+) bacteria and plays a crucial role in priming antigen-specific naïve T cells.

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Cross talk of the first-line defense TLRs with PI3K/Akt pathway, in preconditioning therapeutic approach

Cited by 46 publications

References 81 publications

Novel approaches of pharmacological preconditioning: the role of biglycan and miRNAs

Novel approaches of pharmacological preconditioning: the role of biglycan and miRNAs

Akt activator SC79 stimulates antibacterial nitric oxide generation in human nasal epithelial cells in vitro

Cardiolipin activates antigen‐presenting cells via TLR2‐PI3K‐PKN1‐AKT/p38‐NF‐kB signaling to prime antigen‐specific naïve T cells in mice

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