Abstract
Despite the growing knowledge with regard to the immunomodulatory properties of host defense peptides, their impact on macrophage differentiation and on its associated microbicidal functions is still poorly understood. Here, we demonstrated that the P17, a new cationic antimicrobial peptide from ant venom, induces an alternative phenotype of human monocyte-derived macrophages (h-MDMs). This phenotype is characterized by a C-type lectin receptors (CLRs) signature composed of mannose receptor (MR) and Dectin-1 expression. Concomitantly, this activation is associated to an inflammatory profile characterized by reactive oxygen species (ROS), interleukin (IL)-1β, and TNF-α release. P17-activated h-MDMs exhibit an improved capacity to recognize and to engulf Candida albicans through the overexpression both of MR and Dectin-1. This upregulation requires arachidonic acid (AA) mobilization and the activation of peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor through the leukotriene B4 (LTB4) production. AA/LTB4/PPARγ/Dectin-1-MR signaling pathway is crucial for P17-mediated anti-fungal activity of h-MDMs, as indicated by the fact that the activation of this axis by P17 triggered ROS production and inflammasome-dependent IL-1β release. Moreover, we showed that the increased anti-fungal immune response of h-MDMs by P17 was dependent on intracellular calcium mobilization triggered by the interaction of P17 with pertussis toxin-sensitive G-protein-coupled receptors on h-MDMs. Finally, we also demonstrated that P17-treated mice infected with C. albicans develop less severe gastrointestinal infection related to a higher efficiency of their macrophages to engulf Candida, to produce ROS and IL-1β and to kill the yeasts. Altogether, these results identify P17 as an original activator of the fungicidal response of macrophages that acts upstream PPARγ/CLRs axis and offer new immunomodulatory therapeutic perspectives in the field of infectious diseases.
Highlights
Antimicrobial peptides (AMPs), called host defense peptides (HDPs), are small molecules produced by all living forms including bacteria, insects, plants and vertebrates
We demonstrated that P17-treated mice (P17) promotes alter native activation of the human monocyte-derived macrophages (h-MDMs) characterized simultaneously by a C-type lectin receptors (CLRs) signature composed of mannose receptor (MR) and Dectin-1 and a pro-inflammatory profile
Overall, P17treated h-MDMs displayed a downregulation of membrane receptors characteristics of classical M1 polarization, such as CD11b (Itgam), CD16 (Fcgr3), and CD32 (Fcgr2), which was mirrored by an upregulation of MR (Mrc1), Dectin-1 (Clec7a), DC-SIGN (Cd209), and CD36 (Cd36) alternative activation markers (Figure 1A)
Summary
Antimicrobial peptides (AMPs), called host defense peptides (HDPs), are small molecules produced by all living forms including bacteria, insects, plants and vertebrates. Cationic HDPs have a microbicidal activity against a broad spectrum of pathogens including bacteria, yeast, and viruses They exercise their direct antimicrobial effect essentially by interacting with negatively charged membranes of target cells inducing membrane destabilization and cell death [1, 3, 4]. It was previously described that LL-37 regulates cytokine and chemokine genes expression and protein secretion in human monocytes and macrophages [14,15,16] This AMP promotes directly microbicidal activities of monocytes, macrophages, and neutrophils by increasing pathogen phagocytosis and reactive oxygen species (ROS) release [14, 15, 17,18,19]. Among the HDP-activated GPCRs, the N-formylmethionineleucyl-phenylalanine receptors 1 and 2 (FPR1 and FPR2) and the chemokine receptors are the most involved [27,28,29,30]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
