IL-16 promotes T. whipplei replication by inhibiting phagosome conversion and modulating macrophage activation.
The replication of Tropheryma whipplei (the agent of Whipple's disease) within human macrophages is associated with the expression of IL-16, a cytokine known for its chemotactic and inflammatory properties. In this study, we asked whether IL-16 acts on T. whipplei replication by interfering with the endocytic pathway. We observed that in macrophages, T. whipplei was located within late phagosomes that were unable to fuse with lysosomes; in monocytes, T. whipplei was eliminated in phagolysosomes. Moreover, adding IL-16 to monocytes induced bacterial replication and inhibited phagolysosome formation. On the other hand, blocking IL-16 activity, either with anti-IL-16 antibodies in human macrophages or by using murine IL-16(-/-) bone marrow-derived macrophages, inhibited T. whipplei replication and rescued phagolysosome biogenesis. Furthermore, we propose that IL-16-mediated interference with the endocytic pathway is likely related to macrophage activation. First, IFNγ induced T. whipplei elimination and phagolysosome formation and inhibited IL-16 production by macrophages. Second, the full transcriptional response of murine macrophages to T. whipplei showed that T. whipplei specifically modulated the expression of 231 probes in IL-16(-/-) macrophages. Gene Ontology analysis revealed that 10 of 13 over-represented terms were linked to immune responses, including proinflammatory transcriptional factors of the NF-κB family. Our results demonstrated a previously unreported function for IL-16 in promoting bacterial replication through inhibited phagolysosome biogenesis and modulated macrophage activation program.
URMITE, CNRS UMR 6236-IRD 3R198, Université de la Méditerranée, Marseille, France.
Eric
E
Ghigo
Abdoulaye Oury
AO
Barry
Lionel
L
Pretat
Khatoun
K
Al Moussawi
Benoît
B
Desnues
Christian
C
Capo
Hardy
H
Kornfeld
Jean-Louis
JL
Mege
D000818:Animals; D004705:Endocytosis; D006801:Humans; D019410:Interleukin-16 / Q000502:physiology*; D008262:Macrophage Activation; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010588:Phagosomes; D054851:Tropheryma / Q000254:growth & development*
D019410:Interleukin-16