Signaling Pathways Mediating Chemokine Induction in Keratinocytes by Cathelicidin LL-37 and Flagellin

Nijnik, Anastasia; Pistolic, Jelena; Filewod, Niall; Hancock, Robert E. W.

doi:10.1159/000335901

Cited by 49 publications

(39 citation statements)

References 82 publications

(66 reference statements)

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“…However, this interdependence of PAMP and DAMP signaling on a cellular level also occurs in animal cells. In the case of at least some animal DAMP peptides and flagellin (as discussed above), the cell signaling cascades responding to the perception of these peptides share many molecular steps and act synergistically (Nijnik et al, 2012). Our work with the double NADPH peroxidase mutant rbohD/rbohF notes a difference in the involvement of these ROS-generating proteins in Pep/PEPR and flagellin/FLS2 signaling leading to defense gene expression.…”

Section: Discussionmentioning

confidence: 71%

“…The mechanistic basis for this interdependence of PAMP and plant DAMP signaling at the cellular level is not delineated here; however, it is also not without precedent. Human innate immune responses have been also recently found to include the synergistic amplification of flagellin signaling by an endogenous DAMP peptide; the signaling pathways downstream from the cell membrane flagellin and LL-37 peptide receptors include steps that interact and amplify the immune responses evoked by the individual ligands (Nijnik et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

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Molecular Steps in the Immune Signaling Pathway Evoked by Plant Elicitor Peptides: Ca2+-Dependent Protein Kinases, Nitric Oxide, and Reactive Oxygen Species Are Downstream from the Early Ca2+ Signal

Zhao

Walker

et al. 2013

Plant Physiology

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Endogenous plant elicitor peptides (Peps) can act to facilitate immune signaling and pathogen defense responses. Binding of these peptides to the Arabidopsis (Arabidopsis thaliana) plasma membrane-localized Pep receptors (PEPRs) leads to cytosolic Ca2+ elevation, an early event in a signaling cascade that activates immune responses. This immune response includes the amplification of signaling evoked by direct perception of pathogen-associated molecular patterns by plant cells under assault. Work included in this report further characterizes the Pep immune response and identifies new molecular steps in the signal transduction cascade. The PEPR coreceptor BRASSINOSTEROID-INSENSITIVE1 Associated Kinase1 contributes to generation of the Pep-activated Ca2+ signal and leads to increased defense gene expression and resistance to a virulent bacterial pathogen. Ca2+-dependent protein kinases (CPKs) decode the Ca2+ signal, also facilitating defense gene expression and enhanced resistance to the pathogen. Nitric oxide and reduced nicotinamide adenine dinucleotide phosphate oxidase-dependent reactive oxygen species generation (due to the function of Respiratory Burst Oxidase Homolog proteins D and F) are also involved downstream from the Ca2+ signal in the Pep immune defense signal transduction cascade, as is the case with BRASSINOSTEROID-INSENSITIVE1 Associated Kinase1 and CPK5, CPK6, and CPK11. These steps of the pathogen defense response are required for maximal Pep immune activation that limits growth of a virulent bacterial pathogen in the plant. We find a synergism between function of the PEPR and Flagellin Sensing2 receptors in terms of both nitric oxide and reactive oxygen species generation. Presented results are also consistent with the involvement of the secondary messenger cyclic GMP and a cyclic GMP-activated Ca2+-conducting channel in the Pep immune signaling pathway.

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Section: Discussionmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Molecular Steps in the Immune Signaling Pathway Evoked by Plant Elicitor Peptides: Ca2+-Dependent Protein Kinases, Nitric Oxide, and Reactive Oxygen Species Are Downstream from the Early Ca2+ Signal

Zhao

Walker

et al. 2013

Plant Physiology

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“…The cationic LL-37 molecule binds to negatively charged microbial membrane lipids thereby showing membrane selectivity [3]. Furthermore, LL-37 potentiates chemokine production by microbial stimuli in keratinocytes and other epithelial cells, suggesting that it enhances the immune defense of the skin [7]. …”

Section: Introductionmentioning

confidence: 99%

The Antimicrobial Peptide LL-37 Alters Human Osteoblast Ca<sup>2+</sup> Handling and Induces Ca<sup>2+</sup>-Independent Apoptosis

et al. 2013

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The human antimicrobial peptide cathelicidin LL-37 has, besides its antimicrobial properties, also been shown to regulate apoptosis in a cell type-specific manner. Mechanisms involved in LL-37-regulated apoptotic signaling are not identified. Here, we show that LL-37 reduces the human osteoblast-like MG63 cell number and cell viability in the micromolar concentration range with an IC₅₀ value of about 5 µM. Treatment with 4 µM LL-37 increased the number of annexin V-positive cells and stimulated activation of caspase 3 showing that LL-37 promotes apoptosis. Treatment with 4 µM LL-37 caused an acute and sustained rise in intracellular Ca²⁺ concentration assessed by laser-scanning confocal microscopy of Fluo-4-AM-loaded MG63 cells. LL-37 increased Ca²⁺ also in the presence of the respective L- and T-type voltage-sensitive Ca²⁺ channel blockers nifedipine and NiCl₂. LL-37 had no effect on Ca²⁺ in cells incubated with Ca²⁺-free solution. LL-37 (4 and 8 µM) reduced the MG63 cell number both in the presence and absence of Ca²⁺ in the medium. In conclusion, LL-37 reduces the osteoblast cell number by promoting apoptosis, and furthermore, LL-37 stimulates Ca²⁺ inflow via a mechanism independent of voltage-sensitive Ca²⁺ channels. Interestingly, LL-37-induced lowering of the cell number seems to be mediated via a mechanism independent of Ca²⁺.

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“…First, cathelicidins are well known for their antimicrobial activity, although this activity has been questioned, because many cathelicidins show a reduced antimicrobial activity when tested under more physiological conditions (22,23). Second, cathelicidins have been shown to regulate activation of a wide variety of TLRs, including many mammalian TLRs, which can play an important role in the modulation of the inflammatory response during infections (24)(25)(26)(27)(28)(29). For instance, cathelicidins, such as human LL-37 and chicken cathelicidin-2 (CATH-2), have been shown to inhibit LPS-induced TLR4 activation and to enhance DNA-induced TLR9 or TLR21 activation (23,28).…”

mentioning

confidence: 99%

Cathelicidins Inhibit Escherichia coli–Induced TLR2 and TLR4 Activation in a Viability-Dependent Manner

Coorens

Schneider

Groot

et al. 2017

The Journal of Immunology

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Activation of the immune system needs to be tightly regulated to provide protection against infections and, at the same time, to prevent excessive inflammation to limit collateral damage to the host. This tight regulation includes regulating the activation of TLRs, which are key players in the recognition of invading microbes. A group of short cationic antimicrobial peptides, called cathelicidins, have previously been shown to modulate TLR activation by synthetic or purified TLR ligands and may play an important role in the regulation of inflammation during infections. However, little is known about how these cathelicidins affect TLR activation in the context of complete and viable bacteria. In this article, we show that chicken cathelicidin-2 kills Escherichia coli in an immunogenically silent fashion. Our results show that chicken cathelicidin-2 kills E. coli by permeabilizing the bacterial inner membrane and subsequently binds the outer membrane-derived lipoproteins and LPS to inhibit TLR2 and TLR4 activation, respectively. In addition, other cathelicidins, including human, mouse, pig, and dog cathelicidins, which lack antimicrobial activity under cell culture conditions, only inhibit macrophage activation by nonviable E. coli. In total, this study shows that cathelicidins do not affect immune activation by viable bacteria and only inhibit inflammation when bacterial viability is lost. Therefore, cathelicidins provide a novel mechanism by which the immune system can discriminate between viable and nonviable Gramnegative bacteria to tune the immune response, thereby limiting collateral damage to the host and the risk for sepsis.

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Signaling Pathways Mediating Chemokine Induction in Keratinocytes by Cathelicidin LL-37 and Flagellin

Cited by 49 publications

References 82 publications

Molecular Steps in the Immune Signaling Pathway Evoked by Plant Elicitor Peptides: Ca2+-Dependent Protein Kinases, Nitric Oxide, and Reactive Oxygen Species Are Downstream from the Early Ca2+ Signal

Molecular Steps in the Immune Signaling Pathway Evoked by Plant Elicitor Peptides: Ca2+-Dependent Protein Kinases, Nitric Oxide, and Reactive Oxygen Species Are Downstream from the Early Ca2+ Signal

The Antimicrobial Peptide LL-37 Alters Human Osteoblast Ca<sup>2+</sup> Handling and Induces Ca<sup>2+</sup>-Independent Apoptosis

Cathelicidins Inhibit Escherichia coli–Induced TLR2 and TLR4 Activation in a Viability-Dependent Manner

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