Dataset Information

Antimicrobial Peptide Omiganan Enhances Interferon Responses to Endosomal Toll-Like Receptor Ligands in Human Peripheral Blood Mononuclear Cells.

ABSTRACT: LL-37 is a cationic antimicrobial peptide and the sole human member of cathelicidins. Besides its bactericidal properties, LL-37 is known to have direct immunomodulatory effects, among which enhancement of antiviral responses via endosomal toll-like receptors (TLRs). Omiganan pentahydrochloride is a synthetic cationic peptide in clinical development. Previously, omiganan was primarily known for its direct bactericidal and antifungal properties. We investigated whether omiganan enhances endosomal TLR responses, similar to LL-37. Human peripheral blood mononuclear cells were treated with endosomal TLR3, -7, -8, and -9 ligands in the presence of omiganan. Omiganan enhanced TLR-mediated interferon-? release. Subsequent experiments with TLR9 ligands showed that plasmacytoid dendritic cells were main contributors to omiganan-enhanced IFN production. Based on this type I interferon-enhancing effect, omiganan may qualify as potential treatment modality for virus-driven diseases. The molecular mechanism by which omiganan enhances endosomal TLR responses remains to be elucidated.

SUBMITTER: Grievink HW

PROVIDER: S-EPMC7485948 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Antimicrobial Peptide Omiganan Enhances Interferon Responses to Endosomal Toll-Like Receptor Ligands in Human Peripheral Blood Mononuclear Cells.

Grievink Hendrika W HW Jirka Silvana M G SMG Woutman Tess D TD Schoonakker Mascha M Rissmann Robert R Malone Karen E KE Feiss Gary G Moerland Matthijs M

Clinical and translational science 20200421 5

LL-37 is a cationic antimicrobial peptide and the sole human member of cathelicidins. Besides its bactericidal properties, LL-37 is known to have direct immunomodulatory effects, among which enhancement of antiviral responses via endosomal toll-like receptors (TLRs). Omiganan pentahydrochloride is a synthetic cationic peptide in clinical development. Previously, omiganan was primarily known for its direct bactericidal and antifungal properties. We investigated whether omiganan enhances endosomal ...[more]

PMID: 32314872

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Project description:BACKGROUND:Interferon ? (IFN?) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFN? signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFN? signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFN? modulates these functions are not well defined. METHODS:Using a model of peripheral IFN? administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFN? and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFN? on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry. RESULTS:We found that IFN? exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFN?-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region-specific differences. Finally, by specifically knocking down expression of IFNAR1 on microglia, we show that these changes are largely attributable to direct IFNAR signalling on microglia and not from indirect signalling effects through other CNS parenchymal cell types which are capable of IFN?-IFNAR signal transduction. CONCLUSIONS:Peripheral IFN? induces unique genetic and phenotypic changes in microglia that are largely dependent on direct signalling through microglial IFNAR. The IFN?-induced upregulation of C4b could play important roles in the context of aberrant synaptic pruning in neuropsychiatric disease.

Dataset Information

Antimicrobial Peptide Omiganan Enhances Interferon Responses to Endosomal Toll-Like Receptor Ligands in Human Peripheral Blood Mononuclear Cells.

Publications

Antimicrobial Peptide Omiganan Enhances Interferon Responses to Endosomal Toll-Like Receptor Ligands in Human Peripheral Blood Mononuclear Cells.

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