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The N-formyl peptide receptors: contemporary roles in neuronal function and dysfunction.

ABSTRACT: N-formyl peptide receptors (FPRs) were first identified upon phagocytic leukocytes, but more than four decades of research has unearthed a plethora of non-myeloid roles for this receptor family. FPRs are expressed within neuronal tissues and markedly in the central nervous system, where FPR interactions with endogenous ligands have been implicated in the pathophysiology of several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, as well as neurological cancers such as neuroblastoma. Whilst the homeostatic function of FPRs in the nervous system is currently undefined, a variety of novel physiological roles for this receptor family in the neuronal context have been posited in both human and animal settings. Rapid developments in recent years have implicated FPRs in the process of neurogenesis and neuronal differentiation which, upon greater characterisation, could represent a novel pharmacological target for neuronal regeneration therapies that may be used in the treatment of brain/spinal cord injury, stroke and neurodegeneration. This review aims to summarize the recent progress made to determine the physiological role of FPRs in a neuronal setting, and to put forward a case for FPRs as a novel pharmacological target for conditions of the nervous system, and for their potential to open the door to novel neuronal regeneration therapies.

SUBMITTER: Cussell PJG

PROVIDER: S-EPMC7047793 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The <i>N</i>-formyl peptide receptors: contemporary roles in neuronal function and dysfunction.

Cussell Peter J G PJG Gomez Escalada Margarita M Milton Nathaniel G N NGN Paterson Andrew W J AWJ

Neural regeneration research 20200701 7

N-formyl peptide receptors (FPRs) were first identified upon phagocytic leukocytes, but more than four decades of research has unearthed a plethora of non-myeloid roles for this receptor family. FPRs are expressed within neuronal tissues and markedly in the central nervous system, where FPR interactions with endogenous ligands have been implicated in the pathophysiology of several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, as well as neurological cancers su ...[more]

PMID: 31960798

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Project description:Necrotic cells evoke potent innate immune responses through unclear mechanisms. The mitochondrial fraction of the cell retains constituents of its bacterial ancestors, including N-formyl peptides, which are potentially immunogenic. Thus, we hypothesized that the mitochondrial fraction of the cell, particularly N-formyl peptides, contributes significantly to the activation of monocytes by necrotic cells.Human peripheral blood monocytes were incubated with necrotic cell fractions and mitochondrial proteins to investigate their potential for immune cell activation.University Medical Center Research Laboratory.Healthy human adults served as blood donors.Human blood monocyte activation was measured after treatment with cytosolic, nuclear and mitochondrial fractions of necrotic HepG2 cells or necrotic HepG2 cells depleted of N-formyl peptides [Rho(0) cells]. The specific role of the high affinity formyl peptide receptor (FPR) was then tested using specific pharmacologic inhibitors and RNA silencing. The capacity of mitochondrial N-formyl peptides to activate monocytes was confirmed using a synthetic peptide conforming to the N-terminus of mitochondrial nicotinamide adenine dinucleotide subunit 6. The results demonstrated that mitochondrial cell fractions most potently activated monocytes, and interleukin (IL)-8 was selectively released at low-protein concentrations. Mitochondria from Rho(0) cells induced minimal monocyte IL-8 release, and specific pharmacologic inhibitors and RNA-silencing confirmed that FPR contributes significantly to monocyte IL-8 responses to both necrotic cells and mitochondrial proteins. N-formyl peptides alone did not induce monocyte IL-8 release; whereas, the combination of mitochondrial N-formyl peptides and mitochondrial transcription factor A (TFAM) dramatically increased IL-8 release from monocytes. Likewise, high mobility group box 1, the nuclear homolog of TFAM, did not induce monocyte IL-8 release unless combined with mitochondrial N-formyl peptides.Interactions between mitochondrial N-formyl peptides and FPR in the presence of other mitochondrial antigens (e.g., TFAM) contributes significantly to the activation of monocytes by necrotic cells.

Dataset Information

The N-formyl peptide receptors: contemporary roles in neuronal function and dysfunction.

Publications

The <i>N</i>-formyl peptide receptors: contemporary roles in neuronal function and dysfunction.

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