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Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b(+) Conventional Dendritic Cells and Non-Protective Th2 Bias

Macrophage receptor with collagenous structure (MARCO) contributes to fungal containment during the early/innate phase of cryptococcal infection; however, its role in adaptive antifungal immunity remains unknown. Using a murine model of cryptococcosis, we compared host adaptive immune responses in w...

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Autores principales: Xu, Jintao, Flaczyk, Adam, Neal, Lori M., Fa, Zhenzong, Cheng, Daphne, Ivey, Mike, Moore, Bethany B., Curtis, Jeffrey L., Osterholzer, John J., Olszewski, Michal A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624996/
https://www.ncbi.nlm.nih.gov/pubmed/29033946
http://dx.doi.org/10.3389/fimmu.2017.01231
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author Xu, Jintao
Flaczyk, Adam
Neal, Lori M.
Fa, Zhenzong
Cheng, Daphne
Ivey, Mike
Moore, Bethany B.
Curtis, Jeffrey L.
Osterholzer, John J.
Olszewski, Michal A.
author_facet Xu, Jintao
Flaczyk, Adam
Neal, Lori M.
Fa, Zhenzong
Cheng, Daphne
Ivey, Mike
Moore, Bethany B.
Curtis, Jeffrey L.
Osterholzer, John J.
Olszewski, Michal A.
author_sort Xu, Jintao
collection PubMed
description Macrophage receptor with collagenous structure (MARCO) contributes to fungal containment during the early/innate phase of cryptococcal infection; however, its role in adaptive antifungal immunity remains unknown. Using a murine model of cryptococcosis, we compared host adaptive immune responses in wild-type and MARCO(−/−) mice throughout an extended time course post-infection. Unlike in early infection, MARCO deficiency resulted in improved pulmonary fungal clearance and diminished cryptococcal dissemination during the efferent phase. Improved fungal control in the absence of MARCO expression was associated with enhanced hallmarks of protective Th1-immunity, including higher frequency of pulmonary TNF-α-producing T cells, increased cryptococcal-antigen-triggered IFN-γ and TNF-α production by splenocytes, and enhanced expression of M1 polarization genes by pulmonary macrophages. Concurrently, we found lower frequencies of IL-5- and IL-13-producing T cells in the lungs, impaired production of IL-4 and IL-10 by cryptococcal antigen-pulsed splenocytes, and diminished serum IgE, which were hallmarks of profoundly suppressed efferent Th2 responses in MARCO-deficient mice compared to WT mice. Mechanistically, we found that MARCO expression facilitated early accumulation and alternative activation of CD11b(+) conventional DC (cDC) in the lung-associated lymph nodes (LALNs), which contributed to the progressive shift of the immune response from Th1 toward Th2 at the priming site (LALNs) and local infection site (lungs) during the efferent phase of cryptococcal infection. Taken together, our study shows that MARCO can be exploited by the fungal pathogen to promote accumulation and alternative activation of CD11b(+) cDC in the LALN, which in turn alters Th1/Th2 balance to promote fungal persistence and dissemination.
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spelling pubmed-56249962017-10-13 Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b(+) Conventional Dendritic Cells and Non-Protective Th2 Bias Xu, Jintao Flaczyk, Adam Neal, Lori M. Fa, Zhenzong Cheng, Daphne Ivey, Mike Moore, Bethany B. Curtis, Jeffrey L. Osterholzer, John J. Olszewski, Michal A. Front Immunol Immunology Macrophage receptor with collagenous structure (MARCO) contributes to fungal containment during the early/innate phase of cryptococcal infection; however, its role in adaptive antifungal immunity remains unknown. Using a murine model of cryptococcosis, we compared host adaptive immune responses in wild-type and MARCO(−/−) mice throughout an extended time course post-infection. Unlike in early infection, MARCO deficiency resulted in improved pulmonary fungal clearance and diminished cryptococcal dissemination during the efferent phase. Improved fungal control in the absence of MARCO expression was associated with enhanced hallmarks of protective Th1-immunity, including higher frequency of pulmonary TNF-α-producing T cells, increased cryptococcal-antigen-triggered IFN-γ and TNF-α production by splenocytes, and enhanced expression of M1 polarization genes by pulmonary macrophages. Concurrently, we found lower frequencies of IL-5- and IL-13-producing T cells in the lungs, impaired production of IL-4 and IL-10 by cryptococcal antigen-pulsed splenocytes, and diminished serum IgE, which were hallmarks of profoundly suppressed efferent Th2 responses in MARCO-deficient mice compared to WT mice. Mechanistically, we found that MARCO expression facilitated early accumulation and alternative activation of CD11b(+) conventional DC (cDC) in the lung-associated lymph nodes (LALNs), which contributed to the progressive shift of the immune response from Th1 toward Th2 at the priming site (LALNs) and local infection site (lungs) during the efferent phase of cryptococcal infection. Taken together, our study shows that MARCO can be exploited by the fungal pathogen to promote accumulation and alternative activation of CD11b(+) cDC in the LALN, which in turn alters Th1/Th2 balance to promote fungal persistence and dissemination. Frontiers Media S.A. 2017-09-28 /pmc/articles/PMC5624996/ /pubmed/29033946 http://dx.doi.org/10.3389/fimmu.2017.01231 Text en Copyright © 2017 Xu, Flaczyk, Neal, Fa, Cheng, Ivey, Moore, Curtis, Osterholzer and Olszewski. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Xu, Jintao
Flaczyk, Adam
Neal, Lori M.
Fa, Zhenzong
Cheng, Daphne
Ivey, Mike
Moore, Bethany B.
Curtis, Jeffrey L.
Osterholzer, John J.
Olszewski, Michal A.
Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b(+) Conventional Dendritic Cells and Non-Protective Th2 Bias
title Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b(+) Conventional Dendritic Cells and Non-Protective Th2 Bias
title_full Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b(+) Conventional Dendritic Cells and Non-Protective Th2 Bias
title_fullStr Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b(+) Conventional Dendritic Cells and Non-Protective Th2 Bias
title_full_unstemmed Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b(+) Conventional Dendritic Cells and Non-Protective Th2 Bias
title_short Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Cryptococcus neoformans Promotes Alternative Activation of Pulmonary Lymph Node CD11b(+) Conventional Dendritic Cells and Non-Protective Th2 Bias
title_sort exploitation of scavenger receptor, macrophage receptor with collagenous structure, by cryptococcus neoformans promotes alternative activation of pulmonary lymph node cd11b(+) conventional dendritic cells and non-protective th2 bias
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624996/
https://www.ncbi.nlm.nih.gov/pubmed/29033946
http://dx.doi.org/10.3389/fimmu.2017.01231
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