Hypoxia in Leishmania major Skin Lesions Impairs the NO-Dependent Leishmanicidal Activity of Macrophages
Open accessAbstract
Cure of infections with Leishmania major is critically dependent on the ability of macrophages to induce the type 2 nitic oxide (NO) synthase (NOS2) that produces high levels of NO in the presence of ample oxygen. Therefore, we analyzed the oxygen levels found in leishmanial skin lesions and their effect on the NOS2-dependent leishmanicidal activity of macrophages (MΦ). When L. major skin lesions of self-healing C57BL/6 mice reached their maximum size, the infected tissue displayed low oxygen levels (pO2∼21 Torr). MΦ activated under these oxygen tensions failed to produce sufficient amounts of NO to clear L. major. Nos2-deficient and hypoxic wild-type macrophages displayed a similar phenotype. Killing was restored when MΦ were reoxygenated or exposed to a NO donor. The resolution of the lesion in C57BL/6 mice was paralleled by an increase of lesional pO2. When mice were kept under normobaric hypoxia, this caused a persistent suppression of the lesional pO2 and a concurrent increase of the parasite load. In Nos2-deficient mice, there was no effect of atmospheric hypoxia. Low oxygen levels found at leishmanial skin lesions impaired the NOS2-dependent leishmanicidal activity of MΦ. Hence, tissue oxygenation represents an underestimated local milieu factor that participates in the persistence of Leishmania.
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Hypoxia impairs NO production by Nos2 and thus blunts the antimicrobial activity of macrophages towards Leishmania major.
“Moreover, hypoxia impairs NO production by Nos2 and thus blunts the antimicrobial activity of macrophages towards Leishmania major [142].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [142]
TLR4 signaling stabilizes HIF-1α activation via induction of FTH and hypoxia stimulates arginase-1 expression in myeloid cells thus undermining Leishmania killing.
“Another layer of complexity is added by the fact that TLR4 signaling stabilizes HIF-1α activation via induction of FTH and hypoxia stimulates arginase-1 expression in myeloid cells thus undermining Leishmania killing [142, 209].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [142]
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- Authors
- Mahnke, A., Meier, R. J., Schatz, V., Hofmann, J., Castiglione, K., Schleicher, U., Wolfbeis, O. S., Bogdan, C., & Jantsch, J.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Regensburg (DE)
- Corresponding author
- Jantsch, Jonathan
- ORCID
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 134
- Issue
- 9
- Pages
- 2339-2346
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2085963325
- Cited by
- 69
- References
- 49
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 5 · 2022: 7 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 6 · 2014: 5
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (JA 1993/1-1)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
- Health Sciences › Medicine › Infectious Diseases › Leprosy Research and Treatment
- Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
- Keywords
- Leishmania major, cutaneous leishmaniasis, hypoxia, tissue oxygen tension, nitric oxide, NOS2, parasite clearance, reoxygenation, infection intensity, host-parasite interactions
- MeSH terms
- Animals, Hypoxia, Arginase, Atmosphere Exposure Chambers, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Nitric Oxide, Oxygen, Phenotype, Skin, Leishmaniasis, Cutaneous, Leishmania major, Mice, Knockout, Nitric Oxide Synthase Type II
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