Efficient Capture of Infected Neutrophils by Dendritic Cells in the Skin Inhibits the Early Anti-Leishmania Response

Abstract

Neutrophils and dendritic cells (DCs) converge at localized sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. Prior studies in mice have shown that neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin, and that neutrophil depletion promotes host resistance to sand fly transmitted infection. How the massive influx of neutrophils aimed at wound repair and sterilization might modulate the function of DCs in the skin has not been previously addressed. The infected neutrophils recovered from the skin expressed elevated apoptotic markers compared to uninfected neutrophils, and were preferentially captured by dermal DCs when injected back into the mouse ear dermis. Following challenge with L. major directly, the majority of the infected DCs recovered from the skin at 24 hr stained positive for neutrophil markers, indicating that they acquired their parasites via uptake of infected neutrophils. When infected, dermal DCs were recovered from neutrophil depleted mice, their expression of activation markers was markedly enhanced, as was their capacity to present Leishmania antigens ex vivo. Neutrophil depletion also enhanced the priming of L. major specific CD4+ T cells in vivo. The findings suggest that following their rapid uptake by neutrophils in the skin, L. major exploits the immunosuppressive effects associated with the apoptotic cell clearance function of DCs to inhibit the development of acquired resistance until the acute neutrophilic response is resolved.

Infection and Activation of Human Neutrophils with Fluorescent Leishmania infantum

“…Studies examining interactions between PMNs and Leishmania species show that PMNs take up but do not eliminate all internalized parasites [4,25]. We questioned how internalization of L. infantum would alter the PMNs’ activation status and production of microbicidal compounds such as ROS.…”

“…The mechanisms whereby the parasite is efficiently taken up by and survives within the mammalian phagocyte are critical to disease pathogenesis. Although parasites are found in macrophages through much of infection [2,3], it has become apparent that other cell types may perhaps act as the first haven for parasites within the host [4–8], but how these non-macrophage cell-types interact with Leishmania parasites is less-well understood. Many studies examine early Leishmania-host cell interactions by document responses of mammalian cell populations in bulk culture [9].…”

“…Indeed, there appears to be distinct differences in the way various species of Leishmania result in activation and otherwise affect neutrophils [10,21–23]. In the context of disease progression, it has been suggested that, rather than control the infection, neutrophils exacerbate disease onset either by delaying apoptosis, by impairing activation of dendritic cells, or by serving as a vehicle route for silent entry of the parasite [4,24–26]. …”

Leishmania, the phagosome, and host responses: The journey of a parasite

“…An augmented flux of neutrophils to the wound is therefore quickly established to control the infection [26]. Neutrophils quickly undergo apoptosis and are taken up by macrophages and dentritic cells [27,28].…”

“…Leishmania-harboring apoptotic neutrophils are in turn internalized by dendritic cells, triggering an immunosuppressive response, which delays the development of acquired resistance [28].This uptake of apoptotic neutrophils has been shown to allow L. major survival in the early infection steps, highlighting a mechanism by which L. major exploits the macrophage/dendritic cells-neutrophils interaction [29,30]. Clearance of the infected apoptotic neutrophils by dendritic cells was also shown to lead to the inhibition of CD8+ T cells priming in vitro [31].…”