Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 32, Pages 13087-13096Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M117.780981
Keywords
-
Categories
Funding
- Fundacao de Apoio a Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo
- PewProgram in Biomedical Sciences
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [401577/2014-7, 445881/2014-3]
- Instituto Nacional de Ciencia e Tecnologia em Vacinas (INCTV/CNPq)
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/08216-2, 2014/04684-4]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [14/04684-4] Funding Source: FAPESP
Ask authors/readers for more resources
Leishmaniasis is caused by protozoan parasites of the genus Leishmania. In mammalians, these parasites survive and replicate in macrophages and parasite elimination by macrophages is critical for host resistance. Endosomal Toll-like receptors (TLRs) have been shown to be crucial for resistance to Leishmania major in vivo. For example, mice in the resistant C57BL/6 genetic background that are triple-deficient for TLR3, -7, and -9 (Tlr3/7/9(-/-)) are highly susceptible to L. major infection. Tlr3/7/9(-/-) mice are as susceptible as mice deficient in MyD88 or UNC93B1, a chaperone required for appropriate localization of endosomal TLRs, but the mechanisms are unknown. Here we found that macrophages infected with L. major undergo autophagy, which effectively accounted for restriction of parasite replication. Signaling via endosomal TLRs was required for autophagy because macrophages deficient for TLR3, -7, and 9, UNC93B1, or MyD88 failed to undergo L. major-induced autophagy. We also confirmed that Myd88(-/-), Tlr3/7/9(-/-), and Unc93b1(-/-) cells were highly permissive to L. major replication. Accordingly, shRNA-mediated suppression of Atg5, an E3 ubiquitin ligase essential for autophagosome elongation, in macrophages impaired the restriction of L. major replication in C57BL/6, but did not affect parasite replication in Myd88(-/-) or Unc93b1(-/-) macrophages. Rapamycin treatment reduced inflammatory lesions formed in the ears of Leishmania-infected C57BL/6 and Tlr3/7/9(-/-) mice, indicating that autophagy operates downstream of TLR signaling and is relevant for disease development in vivo. Collectively, our results indicate that autophagy contributes to macrophage resistance to L. major replication, and mechanistically explain the previously described endosomal TLR-mediated resistance to L. major infection.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available