Leishmania Promastigotes Enhance Neutrophil Recruitment through the Production of CXCL8 by Endothelial Cells

Abstract

Endothelial cells represent one of the first cell types encountered by Leishmania promastigotes when inoculated into the skin of the human hosts by the bite of phlebotomine sand flies. However, little is known on their role in the early recruitment of phagocytic cells and in the establishment of the infection. Initially, neutrophils, rapidly recruited to the site of promastigotes deposition, phagocytize Leishmania promastigotes, which elude the killing mechanisms of the host cells, survive, and infect other phagocytic cells. Here, we show that Leishmania promastigotes co-incubated with HMEC-1, a microvascular endothelial cell line, exhibited significant morphological changes and loss of infectivity. Moreover, promastigotes of different Leishmania species stimulated the production of CXCL8 by HMEC-1 in a dose- and TLR4-dependent manner. Interestingly, we observed that the conditioned media from Leishmania-stimulated HMEC-1 cells attracted leukocytes, mostly neutrophils, after 2 h of incubation. After 24 h, a higher percentage of monocytes was detected in conditioned media of unstimulated HMEC-1 cells, whereas neutrophils still predominated in conditioned medium from Leishmania-stimulated cells. The same supernatants did not contain CCL5, a chemokine recruiting T cells and monocytes. On the contrary, inhibition of the production of CCL5 induced by TNF-α was seen. These data indicate that the interaction of Leishmania promastigotes with endothelial cells leads to the production of chemokines and the recruitment of neutrophils, which contribute to the establishment of Leishmania infection.

Neutrophils versus Protozoan Parasites: Plasmodium, Trichomonas, Leishmania, Trypanosoma, and Entameoba

“…Neutrophils quickly phagocytose many promastigotes [147] (Figure 3). However, destruction of promastigotes by neutrophil phagocytosis varies among Leishmania species.…”

Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization

“…During the early stages of Leishmania infection, neutrophils are among the first cells to be recruited to the site of infection, mediated by chemotactic signals such as CXCL-1, 3, 5, and 8, and LTB4, released by infected cells, including macrophages and dendritic cells, as well as the parasite itself, facilitating their migration towards the Leishmania -infected tissue [ 20 , 111 , 112 ].…”

Unrevealing the Mystery of Latent Leishmaniasis: What Cells Can Host Leishmania?

“…Endothelial cell parasitism by Leishmania remains unclear, as only a few studies (some of them older) with conflicting results are currently available [ 113 , 115 , 116 , 123 , 124 ]. However, similar to T. cruzi [ 122 ], it is likely that at least some Leishmania species could be able to infect endothelial cells.…”

“…While a recent in vitro analysis of a human microvascular endothelial cell line (HMEC-1) co-incubated with L. infantum promastigotes reported the absence of internalised parasites [ 116 ], the intracellular localisation of Leishmania has been reported from endothelial cells lining the blood-vessels of the kidney, liver, and colon in visceral leishmaniasis [ 81 , 113 , 114 , 123 ]. However, it should be noted that the accurate localisation of amastigotes in routine histopathology (usually used as the sole detection method in older studies) is challenging and may be less sensitive than immunolabelling, as demonstrated in canine cutaneous leishmaniasis [ 125 ].…”