TLR7 Sensing by Neutrophils Is Critical for the Control of Cutaneous Leishmaniasis

Regli, Ivo B; Passelli, Katiuska; Martínez-Salazar, Berenice; Amore, Jonas; Hurrell, Benjamin P.; Müller, Andreas J.; Tacchini‐Cottier, Fabienne

doi:10.1016/j.celrep.2020.107746

Cited by 30 publications

(25 citation statements)

References 66 publications

(80 reference statements)

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“…To assess TLR recognition of E. bovis-derived antigens (EbAg), HEK cells expressing bovine TLR2 or bovine TLR4 containing an NF-κB luciferase reporter (NF-κB-luc, Promega, Chilworth, Hampshire, UK) were used [56,72,73]. Briefly, HEK-TLR2 or HEK-TLR4 cells were seeded at a density of 2.5 × 10 5 cells in 6-well plates using Dulbecco's Modified Eagle Medium (DMEM Life Technologies, Paisley, Renfrewshire, UK) supplemented with 10% fetal bovine serum (FBS, Life Technologies, Paisley, Renfrewshire, UK) and 1 mg mL −1 Geneticin (Life Technologies, Paisley, Renfrewshire, UK).…”

Section: Tlr Stimulation Assaymentioning

confidence: 99%

The Role of TLR2 and TLR4 in Recognition and Uptake of the Apicomplexan Parasite Eimeria bovis and Their Effects on NET Formation

et al. 2021

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Background: Bovine polymorphonuclear neutrophils (PMN) constitutively express the Toll-like receptors (TLRs) TLR2 and TLR4 and have been shown to generate Neutrophil extracellular traps (NETs) upon exposure to Eimeria bovis. The present work investigated the role of TLR2 and TLR4 in the recognition and uptake of E. bovis sporozoites, IL-8 production and neutrophil extracellular trap (NET) formation. Methods: TLR expression was performed by flow cytometric analysis on PMN exposed to live carboxyfluorescein succinimidyl ester (CFSE)-stained sporozoites. Supernatants of PMN exposed to different E. bovis sporozoite preparations and antigens in the absence or presence of TLR antibodies were assessed for IL-8 secretion. Cells were exposed to sporozoite preparations and assessed for the activation of transcription factor NF-κB using a luciferase reporter assay. Immunofluorescence analysis was done to investigate TLR2 and TLR4 surface expression and NET formation on bovine PMN exposed to vital sporozoites. Results: we observed significantly increased TLR2 and TLR4 expression with a mean increase in expression that was greater for TLR2 than TLR4. This upregulation neither inhibited nor promoted sporozoite phagocytosis by bovine PMN. Live sporozoites together with anti-TLR2 mAb resulted in a significant enhancement of IL-8 production. NF-κB activation was more strongly induced in TLR2-HEK cells than in TLR4/MD2-HEK cells exposed to heat-killed sporozoites and antigens. Immunofluorescence analysis showed TLR-positive signals on the surface of PMN and concomitant NET formation. Conclusions: This is the first report on E. bovis-induced concomitant TLR2 and TLR4 expression during bovine PMN-derived NETosis.

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Section: Tlr Stimulation Assaymentioning

confidence: 99%

The Role of TLR2 and TLR4 in Recognition and Uptake of the Apicomplexan Parasite Eimeria bovis and Their Effects on NET Formation

et al. 2021

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“…While by numbers, neutrophils are an important host cell mainly in the beginning of the infection, their phagocytosis of and activation by L. major seems to have an important impact on subsequent induction of adaptive immunity, and thus the whole course of the infection 51 – 53 . As such, parasite interactions with neutrophils have been shown to activate the immune response 54 , 55 , but also enable the pathogen to hijack immune activatory functions 56 , 57 . Furthermore, neutrophils can, by early pathogen sequestration, inhibit the efficient development of an adaptive immune response 58 , but also serve the parasite as a intermediate host cell enabling the infection of further phagocytes by efferocytosis-like mechanisms 59 .…”

Section: Introductionmentioning

confidence: 99%

Ly6G deficiency alters the dynamics of neutrophil recruitment and pathogen capture during Leishmania major skin infection

Kleinholz

Riek‐Burchardt

Seiß

et al. 2021

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Neutrophils represent one of the first immune cell types recruited to sites of infection, where they can control pathogens by phagocytosis and cytotoxic mechanisms. Intracellular pathogens such as Leishmania major can hijack neutrophils to establish an efficient infection. However the dynamic interactions of neutrophils with the pathogen and other cells at the site of the infection are incompletely understood. Here, we have investigated the role of Ly6G, a homolog of the human CD177 protein, which has been shown to interact with cell adhesion molecules, and serves as a bona fide marker for neutrophils in mice. We show that Ly6G deficiency decreases the initial infection rate of neutrophils recruited to the site of infection. Although the uptake of L. major by subsequently recruited monocytes was tightly linked with the concomitant uptake of neutrophil material, this process was not altered by Ly6G deficiency of the neutrophils. Instead, we observed by intravital 2-photon microscopy that Ly6G-deficient neutrophils entered the site of infection with delayed initial recruitment kinetics. Thus, we conclude that by promoting neutrophils’ ability to efficiently enter the site of infection, Ly6G contributes to the early engagement of intracellular pathogens by the immune system.

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“…Interestingly, differences in neutrophil recruitment were observed depending on the site of infection. Intradermal injection led to a higher infiltration of neutrophils compared to s.c injection, while monocytes were more rapidly recruited following s.c. infection, indicating a site-dependent recruitment of myeloid cells in the skin (75,77). Although most of the sand flies transmit a low dose of Leishmania parasites, needle injection of at least 10 5 Leishmania is required to promote rapid parasite-dependent recruitment of neutrophils (70,74,76), further revealing the importance of sand fly derived components in the recruitment of these cells.…”

Section: The Mechanisms Involved In Early Neutrophil Recruitment To Tmentioning

confidence: 99%

“…These data further demonstrated a complex role for neutrophils in self-healing experimental CL. In addition, the sensing of L. major by neutrophil endosomal TLR7, was shown to be critical for the early regulation of parasite burden and subsequent disease control in L. major LV39 infected C57BL/6 mice (75).…”

Section: Protective Role For Neutrophils In Leishmaniasismentioning

confidence: 99%

The Impact of Neutrophil Recruitment to the Skin on the Pathology Induced by Leishmania Infection

2021

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Leishmania (L.) are obligate intracellular protozoan parasites that cause the leishmaniases, a spectrum of neglected infectious vector-borne diseases with a broad range of clinical manifestations ranging from local cutaneous, to visceral forms of the diseases. The parasites are deposited in the mammalian skin during the blood meal of an infected female phlebotomine sand fly. The skin is a complex organ acting as the first line of physical and immune defense against pathogens. Insults to skin integrity, such as that occurring during insect feeding, induces the local secretion of pro-inflammatory molecules generating the rapid recruitment of neutrophils. At the site of infection, skin keratinocytes play a first role in host defense contributing to the recruitment of inflammatory cells to the infected dermis, of which neutrophils are the first recruited cells. Although neutrophils efficiently kill various pathogens including Leishmania, several Leishmania species have developed mechanisms to survive in these cells. In addition, through their rapid release of cytokines, neutrophils modulate the skin microenvironment at the site of infection, a process shaping the subsequent development of the adaptive immune response. Neutrophils may also be recruited later on in unhealing forms of cutaneous leishmaniasis and to the spleen and liver in visceral forms of the disease. Here, we will review the mechanisms involved in neutrophil recruitment to the skin following Leishmania infection focusing on the role of keratinocytes in this process. We will also discuss the distinct involvement of neutrophils in the outcome of leishmaniasis.

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TLR7 Sensing by Neutrophils Is Critical for the Control of Cutaneous Leishmaniasis

Cited by 30 publications

References 66 publications

The Role of TLR2 and TLR4 in Recognition and Uptake of the Apicomplexan Parasite Eimeria bovis and Their Effects on NET Formation

The Role of TLR2 and TLR4 in Recognition and Uptake of the Apicomplexan Parasite Eimeria bovis and Their Effects on NET Formation

Ly6G deficiency alters the dynamics of neutrophil recruitment and pathogen capture during Leishmania major skin infection

The Impact of Neutrophil Recruitment to the Skin on the Pathology Induced by Leishmania Infection

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