Abstract
BackgroundConsiderable evidence supports the concept of active communication between the nervous and immune systems. One class of such communicators are the neuropeptides (NPs). Recent reports have highlighted the antimicrobial activity of neuropeptides, placing them among the integral components of innate immune defense. This study examined the action of four human neuropeptides: calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), substance P (SP) and somatostatin (SOM), which are accessible in the upper respiratory tract, against two human-specific respiratory pathogens. We studied: (i) neuropeptide-mediated direct antibacterial activity exerted against Moraxella catarrhalis and nontypeable Haemophilus influenzae, and (ii) indirect immunomodulatory role of these neuropeptides in the neutrophil-mediated phagocytosis of indicated pathogens.ResultsWe found that 100 micromolar concentrations of CGRP, NPY, SP, and SOM effectively permeabilized bacterial membranes and showed (except SOM) bactericidal activity against both pathogens. SOM acted only bacteriostatically. However the killing efficacy was dependent on the bactericidal assay used. The rank order of killing NP effect was: NPY ≥ CGRP > SP >> SOM and correlated with their potency to permeabilize bacterial membranes. The killing and permeabilization activity of the analyzed NPs showed significant correlation with several physicochemical properties and amino acid composition of the neuropeptides. M. catarrhalis was more sensitive to neuropeptides than nontypeable H. influenzae.The immunomodulatory bimodal effect of physiological concentrations of CGRP, NPY, and SP on the phagocytic function of human neutrophils against M. catarrhalis and H. influenzae was observed both in the ingestion (pathogen uptake) and reactive oxygen species generation stages. This effect was also dependent on the distinct type of pathogen recognition (opsonic versus nonopsonic).ConclusionsThe present results indicate that neuropeptides such as CGRP, NPY, and SP can effectively participate in the direct and indirect elimination of human-specific respiratory pathogens. Because the studied NPs show both direct and indirect modulating antimicrobial potency, they seem to be important molecules involved in the innate host defense against M. catarrhalis and nontypeable H. influenzae.
Highlights
Considerable evidence supports the concept of active communication between the nervous and immune systems
Rank order of permeabilizing potency of neuropeptides In order to determine the potency of calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), its truncated fragment NPY18–36, SOM and substance P (SP) on permeability of the gram-negative bacteria membrane, a model microorganism, E. coli ML-35p and β-galactosidase assay were used
The time-dependent increase in absorbance at 405 nm in this assay is the result of permeability of both the inner and outer bacterial membranes, confirmed by the intracellular influx of the extracellular dye ONPG that is hydrolyzed by constitutively expressed βgalactosidase [34]
Summary
Considerable evidence supports the concept of active communication between the nervous and immune systems. The peripheral nervous system provides a first line of defense at local sites through the release of neuropeptides (peptide neurotransmitters) from sensory nerves [1]. Sensory neuropeptides such as calcitonin generelated peptide (CGRP) and substance P (SP) as well as autonomic neuropeptide Y (NPY) and somatostatin (SOM) are widely distributed throughout the nervous system [2]. Numerous reports highlighted their role as bioactive molecules that exert immunomodulatory effects on innate and adaptive immune responses. Similarities between the NPs and the endogenous antimicrobial peptides led to the discovery of NPs antimicrobial activity directed against various bacteria and fungi [21,22,23], and place neuropeptides among factors that are capable of forming the local barriers of defense against pathogens
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