AUTHOR=Doz-Deblauwe Émilie , Carreras Florence , Arbues Ainhoa , Remot Aude , Epardaud Mathieu , Malaga Wladimir , Mayau Véronique , Prandi Jacques , Astarie-Dequeker Catherine , Guilhot Christophe , Demangel Caroline , Winter Nathalie TITLE=CR3 Engaged by PGL-I Triggers Syk-Calcineurin-NFATc to Rewire the Innate Immune Response in Leprosy JOURNAL=Frontiers in Immunology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02913 DOI=10.3389/fimmu.2019.02913 ISSN=1664-3224 ABSTRACT=

Mycobacterium leprae, the causative agent of leprosy, is unique amongst human pathogens in its capacity to produce the virulence factor phenolic glycolipid (PGL)-I. In addition to mediating bacterial tropism for neurons, PGL-I interacts with Complement Receptor (CR)3 on macrophages (MPs) to promote infection. We demonstrate here that PGL-I binding to CR3 also enhances bacterial invasion of both polymorphonuclear neutrophils (PMNs) and dendritic cells (DCs). Moreover, in all cell types CR3 engagement by PGL-I activates the Syk tyrosine kinase, inducing calcineurin-dependent nuclear translocation of the transcription factor NFATc. This selectively augments the production of IL-2 by DCs, IL-10 by PMNs and IL-1β by MPs. In intranasally-infected mice PGL-I binding to CR3 heightens mycobacterial phagocytosis by lung PMNs and MPs, and stimulates NFATc-controlled production of Syk-dependent cytokines. Our study thus identifies the CR3-Syk-NFATc axis as a novel signaling pathway activated by PGL-I in innate immune cells, rewiring host cytokine responses to M. leprae.