Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection

ABSTRACT The outcome of cryptococcal pneumonia correlates with local macrophage polarization status, as M1 and M2 polarization marks protective and nonprotective responses, respectively. Overall, pulmonary macrophage polarization status changes over time during a cryptococcal infection. This could h...

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Autores principales:	Michael J. Davis, Tiffany M. Tsang, Yafeng Qiu, Jeremy K. Dayrit, Joudeh B. Freij, Gary B. Huffnagle, Michal A. Olszewski
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1e68d97deeb14a00860b5f031d6f59cd
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spelling	oai:doaj.org-article:1e68d97deeb14a00860b5f031d6f59cd2021-11-15T15:40:05ZMacrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection10.1128/mBio.00264-132150-7511https://doaj.org/article/1e68d97deeb14a00860b5f031d6f59cd2013-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00264-13https://doaj.org/toc/2150-7511ABSTRACT The outcome of cryptococcal pneumonia correlates with local macrophage polarization status, as M1 and M2 polarization marks protective and nonprotective responses, respectively. Overall, pulmonary macrophage polarization status changes over time during a cryptococcal infection. This could have been caused by repolarization of individual macrophages or by a replacement of M2-polarized cells by new M1-polarized cells. To explore the ability of macrophages to change between polarization states, we conducted a series of experiments using in vitro macrophages. Coculture of macrophages with Cryptococcus neoformans resulted in development of a weak M1-like phenotype, with modestly increased inducible nitric oxide synthase (iNOS) but lacking interleukin 6 (IL-6) induction. The C. neoformans-induced M1-like polarization state was plastic, as macrophages stimulated first with C. neoformans and then with gamma interferon (IFN-γ) or IL-4 expressed mRNA polarization patterns similar to those stimulated with cytokines alone. To further evaluate macrophage polarization plasticity, cytokine stimulatory conditions were established which fully polarized macrophages. IFN-γ and IL-4 stimulation differentially induced complete M1 and M2 polarization, defined by differential expression of marker mRNA panels, surface marker expression, and tumor necrosis factor alpha (TNF-α) protein production. Switching IFN-γ- to IL-4-stimulating conditions, and vice versa, resulted in uniform changes in profiles of polarization marker genes consistent with the most recent cytokine environment. Furthermore, the ability of sequentially stimulated macrophages to inhibit C. neoformans reflected the most recent polarizing condition, independent of previous polarization. Collectively, these data indicate that M1/M2 macrophage polarization phenotypes are highly plastic to external signals, and interventions which therapeutically repolarize macrophages could be beneficial for treatment of cryptococcosis. IMPORTANCE Our studies reveal how a major opportunistic fungal pathogen, Cryptococcus neoformans, interacts with macrophages, immune cells which can ingest and kill invading pathogens. Macrophages play a crucial role in the pathogenesis of cryptococcal infection, as their polarization phenotype determines the outcome of the battle between the infected host and C. neoformans. This study suggests that dynamic changes in polarization of macrophages at the level of individual cells are an important characteristic of in vivo cryptococcosis, as they occur throughout the natural course of infection. We demonstrate that macrophages can rapidly and uniformly reverse their polarization phenotype in response to dynamic signaling conditions and lose or regain their fungicidal function. Demonstrating importance of these pathways may become a cornerstone for novel therapeutic strategies for treatment of cryptococcosis in both immunocompromised and immunocompetent patients.Michael J. DavisTiffany M. TsangYafeng QiuJeremy K. DayritJoudeh B. FreijGary B. HuffnagleMichal A. OlszewskiAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 3 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Michael J. Davis Tiffany M. Tsang Yafeng Qiu Jeremy K. Dayrit Joudeh B. Freij Gary B. Huffnagle Michal A. Olszewski Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection
description	ABSTRACT The outcome of cryptococcal pneumonia correlates with local macrophage polarization status, as M1 and M2 polarization marks protective and nonprotective responses, respectively. Overall, pulmonary macrophage polarization status changes over time during a cryptococcal infection. This could have been caused by repolarization of individual macrophages or by a replacement of M2-polarized cells by new M1-polarized cells. To explore the ability of macrophages to change between polarization states, we conducted a series of experiments using in vitro macrophages. Coculture of macrophages with Cryptococcus neoformans resulted in development of a weak M1-like phenotype, with modestly increased inducible nitric oxide synthase (iNOS) but lacking interleukin 6 (IL-6) induction. The C. neoformans-induced M1-like polarization state was plastic, as macrophages stimulated first with C. neoformans and then with gamma interferon (IFN-γ) or IL-4 expressed mRNA polarization patterns similar to those stimulated with cytokines alone. To further evaluate macrophage polarization plasticity, cytokine stimulatory conditions were established which fully polarized macrophages. IFN-γ and IL-4 stimulation differentially induced complete M1 and M2 polarization, defined by differential expression of marker mRNA panels, surface marker expression, and tumor necrosis factor alpha (TNF-α) protein production. Switching IFN-γ- to IL-4-stimulating conditions, and vice versa, resulted in uniform changes in profiles of polarization marker genes consistent with the most recent cytokine environment. Furthermore, the ability of sequentially stimulated macrophages to inhibit C. neoformans reflected the most recent polarizing condition, independent of previous polarization. Collectively, these data indicate that M1/M2 macrophage polarization phenotypes are highly plastic to external signals, and interventions which therapeutically repolarize macrophages could be beneficial for treatment of cryptococcosis. IMPORTANCE Our studies reveal how a major opportunistic fungal pathogen, Cryptococcus neoformans, interacts with macrophages, immune cells which can ingest and kill invading pathogens. Macrophages play a crucial role in the pathogenesis of cryptococcal infection, as their polarization phenotype determines the outcome of the battle between the infected host and C. neoformans. This study suggests that dynamic changes in polarization of macrophages at the level of individual cells are an important characteristic of in vivo cryptococcosis, as they occur throughout the natural course of infection. We demonstrate that macrophages can rapidly and uniformly reverse their polarization phenotype in response to dynamic signaling conditions and lose or regain their fungicidal function. Demonstrating importance of these pathways may become a cornerstone for novel therapeutic strategies for treatment of cryptococcosis in both immunocompromised and immunocompetent patients.
format	article
author	Michael J. Davis Tiffany M. Tsang Yafeng Qiu Jeremy K. Dayrit Joudeh B. Freij Gary B. Huffnagle Michal A. Olszewski
author_facet	Michael J. Davis Tiffany M. Tsang Yafeng Qiu Jeremy K. Dayrit Joudeh B. Freij Gary B. Huffnagle Michal A. Olszewski
author_sort	Michael J. Davis
title	Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection
title_short	Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection
title_full	Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection
title_fullStr	Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection
title_full_unstemmed	Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection
title_sort	macrophage m1/m2 polarization dynamically adapts to changes in cytokine microenvironments in <named-content content-type="genus-species">cryptococcus neoformans</named-content> infection
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/1e68d97deeb14a00860b5f031d6f59cd
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Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection

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