CR3 engaged by PGL-I triggers Syk-calcineurin-NFATc to rewire the innate immune response in Leprosy.

Emilie Doz-Deblauwe (1) , Florence Carreras (1) , Ainhoa Arbues (2) , Aude Remot (1) , Mathieu Epardaud (1) , Wladimir Malaga (2) , Véronique Mayau (3) , Jacques Prandi (2) , Catherine Astarie-Dequeker (2) , Christophe Guilhot (2) , Caroline Demangel (3) , Nathalie Winter (1)

1 UMR ISP - Infectiologie et Santé Publique
2 IPBS - Institut de pharmacologie et de biologie structurale
3 Immunobiologie de l'Infection - Immunobiology of Infection

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.

Mots clés: CR3; Mycobacterium leprae; Syk; phenol glycolipid-1

Mots clés: NFAT; dendritic cell; macrophage; neutrophil

Domaines: Immunologie; Microbiologie et Parasitologie

Emilie Doz-Deblauwe, Florence Carreras, Ainhoa Arbues, Aude Remot, Mathieu Epardaud, et al.. CR3 engaged by PGL-I triggers Syk-calcineurin-NFATc to rewire the innate immune response in Leprosy.. Frontiers in Immunology, 2019, 10, 15 p. ⟨10.3389/fimmu.2019.02913⟩. ⟨hal-02624164⟩