Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity
Local tissue acidosis affects anti-tumor immunity. In contrast, data on tissue pH levels in infected tissues and their impact on antimicrobial activity is sparse. In this study, we assessed the pH levels in cutaneous Leishmania lesions. Leishmania major-infected skin tissue displayed pH levels of 6....
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.789366/full |
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| author | Linus Frick Linda Hinterland Kathrin Renner Kathrin Renner Marion Vogl Nathalie Babl Nathalie Babl Simon Heckscher Anna Weigert Susanne Weiß Joachim Gläsner Raffaela Berger Peter J. Oefner Katja Dettmer Marina Kreutz Marina Kreutz Valentin Schatz Jonathan Jantsch |
| author_facet | Linus Frick Linda Hinterland Kathrin Renner Kathrin Renner Marion Vogl Nathalie Babl Nathalie Babl Simon Heckscher Anna Weigert Susanne Weiß Joachim Gläsner Raffaela Berger Peter J. Oefner Katja Dettmer Marina Kreutz Marina Kreutz Valentin Schatz Jonathan Jantsch |
| author_sort | Linus Frick |
| collection | DOAJ |
| description | Local tissue acidosis affects anti-tumor immunity. In contrast, data on tissue pH levels in infected tissues and their impact on antimicrobial activity is sparse. In this study, we assessed the pH levels in cutaneous Leishmania lesions. Leishmania major-infected skin tissue displayed pH levels of 6.7 indicating that lesional pH is acidic. Next, we tested the effect of low extracellular pH on the ability of macrophages to produce leishmanicidal NO and to fight the protozoan parasite Leishmania major. Extracellular acidification led to a marked decrease in both NO production and leishmanicidal activity of lipopolysaccharide (LPS) and interferon γ (IFN-γ)-coactivated macrophages. This was not directly caused by a disruption of NOS2 expression, a shortage of reducing equivalents (NAPDH) or substrate (L-arginine), but by a direct, pH-mediated inhibition of NOS2 enzyme activity. Normalization of intracellular pH significantly increased NO production and antiparasitic activity of macrophages even in an acidic microenvironment. Overall, these findings indicate that low local tissue pH can curtail NO production and leishmanicidal activity of macrophages. |
| first_indexed | 2024-04-13T17:04:58Z |
| format | Article |
| id | doaj.art-3a7a69f7b3644f4f80e2f827ae3a20e3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T17:04:58Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-3a7a69f7b3644f4f80e2f827ae3a20e32022-12-22T02:38:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-04-011310.3389/fimmu.2022.789366789366Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage ActivityLinus Frick0Linda Hinterland1Kathrin Renner2Kathrin Renner3Marion Vogl4Nathalie Babl5Nathalie Babl6Simon Heckscher7Anna Weigert8Susanne Weiß9Joachim Gläsner10Raffaela Berger11Peter J. Oefner12Katja Dettmer13Marina Kreutz14Marina Kreutz15Valentin Schatz16Jonathan Jantsch17Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, GermanyInstitute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyLeibniz Institute for Immunotherapy, Regensburg, GermanyInstitute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyLeibniz Institute for Immunotherapy, Regensburg, GermanyInstitute of Functional Genomics, University of Regensburg, Regensburg, GermanyInstitute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, GermanyInstitute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, GermanyInstitute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, GermanyInstitute of Functional Genomics, University of Regensburg, Regensburg, GermanyInstitute of Functional Genomics, University of Regensburg, Regensburg, GermanyInstitute of Functional Genomics, University of Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyLeibniz Institute for Immunotherapy, Regensburg, GermanyInstitute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, GermanyInstitute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, GermanyLocal tissue acidosis affects anti-tumor immunity. In contrast, data on tissue pH levels in infected tissues and their impact on antimicrobial activity is sparse. In this study, we assessed the pH levels in cutaneous Leishmania lesions. Leishmania major-infected skin tissue displayed pH levels of 6.7 indicating that lesional pH is acidic. Next, we tested the effect of low extracellular pH on the ability of macrophages to produce leishmanicidal NO and to fight the protozoan parasite Leishmania major. Extracellular acidification led to a marked decrease in both NO production and leishmanicidal activity of lipopolysaccharide (LPS) and interferon γ (IFN-γ)-coactivated macrophages. This was not directly caused by a disruption of NOS2 expression, a shortage of reducing equivalents (NAPDH) or substrate (L-arginine), but by a direct, pH-mediated inhibition of NOS2 enzyme activity. Normalization of intracellular pH significantly increased NO production and antiparasitic activity of macrophages even in an acidic microenvironment. Overall, these findings indicate that low local tissue pH can curtail NO production and leishmanicidal activity of macrophages.https://www.frontiersin.org/articles/10.3389/fimmu.2022.789366/fullpHLeishmaniamacrophagesNONOS2 |
| spellingShingle | Linus Frick Linda Hinterland Kathrin Renner Kathrin Renner Marion Vogl Nathalie Babl Nathalie Babl Simon Heckscher Anna Weigert Susanne Weiß Joachim Gläsner Raffaela Berger Peter J. Oefner Katja Dettmer Marina Kreutz Marina Kreutz Valentin Schatz Jonathan Jantsch Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity Frontiers in Immunology pH Leishmania macrophages NO NOS2 |
| title | Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity |
| title_full | Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity |
| title_fullStr | Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity |
| title_full_unstemmed | Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity |
| title_short | Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity |
| title_sort | acidic microenvironments found in cutaneous leishmania lesions curtail no dependent antiparasitic macrophage activity |
| topic | pH Leishmania macrophages NO NOS2 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.789366/full |
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