Leishmania majorinduces distinct neutrophil phenotypes in mice that are resistant or susceptible to infection

Abstract

Polymorphonuclear neutrophils (PMN) are key components of the inflammatory response contributing to the development of pathogen-specific immune responses. Following infection with Leishmania major, neutrophils are recruited within hours to the site of parasite inoculation. C57BL/6 mice are resistant to infection, and BALB/c mice are susceptible to infection, developing unhealing, inflammatory lesions. In this report, we investigated the expression of cell surface integrins, TLRs, and the secretion of immunomodulatory cytokines by PMN of both strains of mice, in response to infection with L. major. The parasite was shown to induce CD49d expression in BALB/c-inflammatory PMN, and expression of CD49d remained at basal levels in C57BL/6 PMN. Equally high levels of CD11b were expressed on PMN from both strains. In response to L. major infection, the levels of TLR2, TLR7, and TLR9 mRNA were significantly higher in C57BL/6 than in BALB/c PMN. C57BL/6 PMN secreted biologically active IL-12p70 and IL-10. In contrast, L. major-infected BALB/c PMN transcribed and secreted high levels of IL-12p40 but did not secrete biologically active IL-12p70. Furthermore, IL-12p40 was shown not to associate with IL-23 p19 but formed IL-12p40 homodimers with inhibitory activity. No IL-10 was secreted by BALB/c PMN. Thus, following infection with L. major, in C57BL/6 mice, PMN could constitute one of the earliest sources of IL-12, and in BALB/c mice, secretion of IL-12p40 could contribute to impaired, early IL-12 signaling. These distinct PMN phenotypes may thus influence the development of L. major-specific immune response.

Human mucosal leishmaniasis: Neutrophils infiltrate areas of tissue damage that express high levels of Th17‐related cytokines

“…Because Th17-driven inflammation is classically characterised by neutrophil infiltration [19], we investigated the presence of these cells in ML lesions. Neutrophils were observed in all ML lesions with varying frequency between patients.…”

“…In experimental cutaneous leishmaniasis, lesion progression is related to IL-17-mediated neutrophil recruitment, whereas improved disease outcome is associated with decreased neutrophil immigration in IL-17-deficient mice [8]. However, neutrophils contribute to parasite clearance in the early steps of experimental leishmania infection [19] and activate macrophages to kill L. major by a mechanism that requires NE [20]. Thus, the presence of neutrophils in this inflammatory context can be indicative of either protection or injury.…”

A Subset of Neutrophils Expressing Markers of Antigen-Presenting Cells in Human Visceral Leishmaniasis

“…Although most parasites reside in macrophages throughout chronic infection, recent studies document the fact that neutrophils are rapidly recruited to the inoculation site, where they internalize parasites. The ultimate impact of neutrophils on the outcome of leishmaniasis remains controversial, in part owing to different methods used for neutrophil depletion and the use of different parasite species and mouse strains in studies [4,5]. Nonetheless, several studies support the observation that neutrophils help the parasite establish infection [6].…”

Neutrophils and Macrophages Cooperate in Host Resistance againstLeishmania braziliensisInfection

“…It was proposed that interactions of apoptotic neutrophils with L. major-infected macrophages from susceptible mice induced an antiinflammatory response, indicated by the presence of de-activating mediators such as TGF-␤ and PGE 2 (10). Moreover, neutrophils infected with L. major display distinct phenotypes that could, in turn, influence the development of the host's immune response (12). However, the control of cutaneous leishmaniasis caused by L. major and Lb differs (13) and the role of neutrophils during infection with Lb has not been investigated to date.…”