Permissive and protective roles for neutrophils in leishmaniasis

Carlsen, Eric D.; Liang, Yuejin; Shelite, Thomas R.; Walker, David H.; Melby, Peter C.; Soong, Lynn

doi:10.1111/cei.12674

Cited by 65 publications

(68 citation statements)

References 98 publications

(145 reference statements)

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“…The short half-life of neutrophils makes it hard to isolate neutrophils from intestines, as it requires a long processing time, and thus most neutrophils isolated would have died by the end of preparation. We thus use peritoneal neutrophils as they are ready to be prepared in large quantities in our in vitro studies (22). We stimulated peritoneal neutrophils with IL-23, IL-6, IL-21, TNFα, or IL-1β to assess which cytokine(s) trigger IL-17 and IL-22 production in neutrophils.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production

Chen

Cao

Yao

et al. 2016

The Journal of Immunology

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It has been shown recently that neutrophils are able to produce IL-22 and IL-17, which differentially regulate the pathogenesis of inflammatory bowel disease (IBD). However, it is still largely unknown how the neutrophil production of IL-22 and IL-17 is regulated, and their role in the pathogenesis of IBD. In this study, we found that IL-23 promoted neutrophil production of IL-17 and IL-22. IL-23 stimulated the neutrophil expression of IL-23 receptor as well as rorc and ahr. RORγt and AhR differentially regulated IL-23 induction of neutrophil IL-17 and IL-22. Additionally, IL-23 induced the activation of mTOR in neutrophils. Blockade of mTOR pathway inhibited IL-23-induced expression of rorc and ahr as well as IL-17 and IL-22 production. By utilizing a microbiota antigen specific T-cell mediated colitis model, we demonstrated that depletion of neutrophils, as well as blockade of IL-22, resulted in a significant increase in the severity of colitis, thereby indicating a protective role of neutrophils and IL-22 in chronic colitis. Collectively, our data revealed that neutrophils negatively regulate microbiota antigen specific T cell induction of colitis, and IL-23 induces neutrophil production of IL-22 and IL-17 through induction of rorc and ahr, which is mediated by mTOR pathway.

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Section: Resultsmentioning

confidence: 99%

“…The neutrophils were prepared from the peritoneal cavity as we previously described (22). Briefly, C57BL/6 mice were injected with 1ml of 3% thioglycollate broth, and the peritoneal cavity was washed with cold PBS buffer containing 5% FBS 5 hours later.…”

Section: Methodsmentioning

confidence: 99%

mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production

Chen

Cao

Yao

et al. 2016

The Journal of Immunology

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“…The results were shown to vary depending on the Leishmania spp. and the genetic background of the host, reviewed in Hurrell et al [11] and Carlsen et al [15]. With the use of L. mexicana parasites, a New World Leishmania spp., we have previously shown that the early neutrophil recruitment following infection has a negative impact on disease outcome, contributing to the development of chronic lesions; associated absence of an efficient, protective immune response; and failure to control parasite load [7].…”

Section: Introductionmentioning

confidence: 99%

Frontline Science: Leishmania mexicana amastigotes can replicate within neutrophils

Hurrell

Beaumann

Heyde

et al. 2017

Journal of Leukocyte Biology

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Cutaneous leishmaniasis is a neglected tropical disease, causing a spectrum of clinical manifestations varying from self-healing to unhealing lesions that may be very difficult to treat. Emerging evidence points to a detrimental role for neutrophils during the first hours following infection with many distinct species (spp.) at a time when the parasite is in its nonreplicative promastigote form. Neutrophils have also been detected at later stages of infection in unhealing chronic cutaneous lesions. However, the interactions between these cells and the replicative intracellular amastigote form of the parasite have been poorly studied. Here, we show that amastigotes are efficiently internalized by neutrophils and that this process has only a low impact on neutrophil activation and apoptosis. In neutrophils, the amastigotes were found in acidified vesicles. Furthermore, within cutaneous unhealing lesions, heavily infected neutrophils were found with up to 6 parasites per cell. To investigate if the amastigotes could replicate within neutrophils, we generated photoconvertible fluorescent parasites. With the use of flow cytometry imaging and time-lapse microscopy, we could demonstrate that a subset of parasites replicated within neutrophils. Overall, our data reveal a novel role for neutrophils that can act as a niche for parasite replication during the chronic phase of infection, thereby contributing to disease pathology.

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“…(12)]. Neutrophil function in human CL has been investigated in several studies (13–15) and they indicate that neutrophils are active players in patients with both acute and chronic CL and are important immune regulators that can have beneficial as well as detrimental effects (16). Since different Leishmania species can drive distinct neutrophil functions (17), it is of utmost importance that the phenotypes and functions of neutrophils isolated from patients infected by different Leishmania species are investigated.…”

Section: Introductionmentioning

confidence: 99%

Visceral Leishmaniasis Patients Display Altered Composition and Maturity of Neutrophils as well as Impaired Neutrophil Effector Functions

et al. 2016

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Immunologically, active visceral leishmaniasis (VL) is characterized by profound immunosuppression, severe systemic inflammatory responses, and an impaired capacity to control parasite replication. Neutrophils are highly versatile cells, which play a crucial role in the induction as well as the resolution of inflammation, the control of pathogen replication, and the regulation of immune responses. Neutrophil functions have been investigated in human cutaneous leishmaniasis; however, their role in human VL is poorly understood. In the present study we evaluated the activation status and effector functions of neutrophils in patients with active VL and after successful anti-leishmanial treatment. Our results show that neutrophils are highly activated and have degranulated; high levels of arginase, myeloperoxidase, and elastase, all contained in neutrophils’ granules, were found in the plasma of VL patients. In addition, we show that a large proportion of these cells are immature. We also analyzed effector functions of neutrophils that are essential for pathogen clearance and show that neutrophils have an impaired capacity to release neutrophil extracellular traps, produce reactive oxygen species, and phagocytose bacterial particles, but not Leishmania parasites. Our results suggest that impaired effector functions, increased activation, and immaturity of neutrophils play a key role in the pathogenesis of VL.

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Permissive and protective roles for neutrophils in leishmaniasis

Cited by 65 publications

References 98 publications

mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production

mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production

Frontline Science: Leishmania mexicana amastigotes can replicate within neutrophils

Visceral Leishmaniasis Patients Display Altered Composition and Maturity of Neutrophils as well as Impaired Neutrophil Effector Functions

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