P17, an Original Host Defense Peptide from Ant Venom, Promotes Antifungal Activities of Macrophages through the Induction of C-Type Lectin Receptors Dependent on LTB4-Mediated PPARγ Activation

Khaddouj Benmoussa (1, 2) , Hélène Authier (1, 3) , Mélissa Prat (1) , Mohammad Alaeddine (1) , Lise Lefèvre (1, 3) , Mouna Chirine Rahabi (1) , José Bernad (1) , Agnès Aubouy (1) , Elsa Bonnafé (2) , Jérôme Leprince (4, 5) , Bernard Pipy (1) , Michel Treilhou (2) , Agnès Coste (3, 1)

1 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement
2 BTSB - Biochimie et Toxicologie des Substances Bioactives
3 Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses
4 Neuroendocrinologie cellulaire et moléculaire
5 DC2N - Différenciation et communication neuronale et neuroendocrine

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.

Mots clés: inflammasome; host defense peptide; arachidonic acid metabolism; Candida albicans; Macrophages; antimicrobial peptides; c-type lectin receptors; PParγ

Domaines: Chimie thérapeutique; Interactions cellulaires [q-bio.CB]; Neurobiologie; Pharmacologie

Khaddouj Benmoussa, Hélène Authier, Mélissa Prat, Mohammad Alaeddine, Lise Lefèvre, et al.. P17, an Original Host Defense Peptide from Ant Venom, Promotes Antifungal Activities of Macrophages through the Induction of C-Type Lectin Receptors Dependent on LTB4-Mediated PPARγ Activation. Frontiers in Immunology, 2017, 8, pp.1650. ⟨10.3389/fimmu.2017.01650⟩. ⟨hal-01960700⟩