Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Abstract

Synaptotagmins (Syts) are type-I membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. We recently discovered that Syt XI is a recycling endosome- and lysosome-associated protein that negatively regulates the secretion of TNF and IL-6. In this study, we show that Syt XI is directly degraded by the zinc metalloprotease GP63 and excluded from Leishmania parasitophorous vacuoles by the promastigotes surface glycolipid lipophosphoglycan. Infected macrophages were found to release TNF and IL-6 in a GP63-dependent manner. To demonstrate that cytokine release was dependent on GP63-mediated degradation of Syt XI, small interfering RNA-mediated knockdown of Syt XI before infection revealed that the effects of small interfering RNA knockdown and GP63 degradation were not cumulative. In mice, i.p. injection of GP63-expressing parasites led to an increase in TNF and IL-6 secretion and to an augmented influx of neutrophils and inflammatory monocytes to the inoculation site. Both of these cell types have been shown to be infection targets and aid in the establishment of infection. In sum, our data revealed that GP63 induces proinflammatory cytokine release and increases infiltration of inflammatory phagocytes. This study provides new insight on how Leishmania exploits the immune response to establish infection.

Exploitation of the Host Cell Membrane Fusion Machinery by Leishmania Is Part of the Infection Process

“…Upon internalization of the parasites, GP63 and LPG are rapidly redistributed throughout infected cells (Fig 1). Akin to the clostridial neurotoxins, GP63 cleaves components of the host cell membrane fusion machinery, including VAMP3, VAMP8, and Syt XI (Table 1) [10, 15]. The consequences of these cleavage events are diverse.…”

“…Consistent with the role of Syt XI as a negative regulator of cytokine secretion, cleavage of this endosomal protein by GP63 from L . major promastigotes increases the postinfection release of TNF and IL-6 [15]. These proinflammatory cytokines are responsible for the augmentation of neutrophil and inflammatory monocyte influx to the parasite inoculation site, which contributes to the spread and maintenance of infection.…”

Synaptotagmin‐11 inhibits cytokine secretion and phagocytosis in microglia

“…Syts are best known as regulators of exocytosis and endocytosis in brain and endocrine cells (Gustavsson & Han, ). Recent studies have revealed that Syt11 regulates phagocytosis and cytokine secretion in macrophages and is required for lysosomal exocytosis in astrocytes (Arango Duque, Fukuda, & Descoteaux, ; Arango Duque, Fukuda, Turco, Stager, & Descoteaux, ; Sreetama, Takano, Nedergaard, Simon, & Jaiswal, ). Importantly, Syt11 is associated with PD and is a candidate gene for susceptibility to schizophrenia (Bento, Ashkenazi, Jimenez‐Sanchez, & Rubinsztein, ; Huynh, Scoles, Nguyen, & Pulst, ; Inoue et al, ; International Parkinson Disease Genomics et al, ; Sesar et al, ; Usenovic et al, ).…”

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

“…Both cell types are infection targets and essential for the establishment of Leishmania infection (45)(46)(47). In the case of Leishmania infections, the release of TNF-␣ and IL-6 by the parasite secretory protein GP63 has been directly associated with inflammatory phagocyte (neutrophil and monocyte) recruitment (40). Thus, it may be hypothesized that the secretion of TNF-␣ and IL-6 by LdTyrRS also contributes toward the accrual of neutrophils at the site of Leishmania infection.…”