A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis
To determine the role that the IL-4/IL13 receptor plays in the development of alternatively activated macrophages (AAM or M2) and their role in the regulation of immunity to the extraintestinal phase of the helminth parasite <i>Taenia crassiceps</i>, we followed the infection in a mouse...
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MDPI AG
2024-02-01
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| Online Access: | https://www.mdpi.com/2076-0817/13/2/169 |
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| author | Jonadab E. Olguín Edmundo Corano-Arredondo Victoria Hernández-Gómez Irma Rivera-Montoya Mario A. Rodríguez Itzel Medina-Andrade Berenice Arendse Frank Brombacher Luis I. Terrazas |
| author_facet | Jonadab E. Olguín Edmundo Corano-Arredondo Victoria Hernández-Gómez Irma Rivera-Montoya Mario A. Rodríguez Itzel Medina-Andrade Berenice Arendse Frank Brombacher Luis I. Terrazas |
| author_sort | Jonadab E. Olguín |
| collection | DOAJ |
| description | To determine the role that the IL-4/IL13 receptor plays in the development of alternatively activated macrophages (AAM or M2) and their role in the regulation of immunity to the extraintestinal phase of the helminth parasite <i>Taenia crassiceps</i>, we followed the infection in a mouse strain lacking the IL-4Rα gene (IL-4Rα<sup>−/−</sup>) and in the macrophage/neutrophil-specific IL-4Rα-deficient mouse strain (LysMcreIL-4Rα<sup>−/lox</sup> or cre/LoxP). While 100% of <i>T. crassiceps</i>-infected IL-4Rα<sup>+/+</sup> (WT) mice harbored large parasite loads, more than 50% of th eIL-4Rα<sup>−/−</sup> mice resolved the infection. Approximately 88% of the LysMcreIL-4Rα<sup>−/lox</sup> mice displayed a sterilizing immunity to the infection. The remaining few infected cre/LoxP mice displayed the lowest number of larvae in their peritoneal cavity. The inability of the WT mice to control the infection was associated with antigen-specific Th2-type responses with higher levels of IgG1, IL-4, IL-13, and total IgE, reduced NO production, and increased arginase activity. In contrast, IL-4Rα<sup>−/−</sup> semi-resistant mice showed a Th1/Th2 combined response. Furthermore, macrophages from the WT mice displayed higher transcripts for Arginase-1 and RELM-α, as well as increased expression of PD-L2 with robust suppressive activity over anti-CD3/CD28 stimulated T cells; all of these features are associated with the AAM or M2 macrophage phenotype. In contrast, both the IL-4Rα<sup>−/−</sup> and LysMcreIL-4Rα<sup>−/lox</sup> mice did not fully develop AAM or display suppressive activity over CD3/CD28 stimulated T cells, reducing PDL2 expression. Additionally, T-CD8<sup>+</sup> but no T-CD4<sup>+</sup> cells showed a suppressive phenotype with increased Tim-3 and PD1 expression in WT and IL-4Rα<sup>−/−</sup>, which were absent in <i>T. crassiceps</i>-infected LysMcreIL-4Rα<sup>−/lox</sup> mice. These findings demonstrate a critical role for the IL-4 signaling pathway in sustaining AAM and its suppressive activity during cysticercosis, suggesting a pivotal role for AAM in favoring susceptibility to <i>T. crassiceps</i> infection. Thus, the absence of these suppressor cells is one of the leading mechanisms to control experimental cysticercosis successfully. |
| first_indexed | 2024-03-07T22:18:51Z |
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| institution | Directory Open Access Journal |
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| last_indexed | 2024-03-07T22:18:51Z |
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| spelling | doaj.art-cf002de4209b44d487e4f4e4070bb8362024-02-23T15:30:25ZengMDPI AGPathogens2076-08172024-02-0113216910.3390/pathogens13020169A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental CysticercosisJonadab E. Olguín0Edmundo Corano-Arredondo1Victoria Hernández-Gómez2Irma Rivera-Montoya3Mario A. Rodríguez4Itzel Medina-Andrade5Berenice Arendse6Frank Brombacher7Luis I. Terrazas8Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Estado de México, MexicoLaboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Estado de México, MexicoLaboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Estado de México, MexicoUnidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Estado de México, MexicoUnidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Estado de México, MexicoCenter for Infectious Medicine (CIM), Department of Medicine, Hudinge, Karolinska Institutet, 141 52 Stockholm, SwedenInstitute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South AfricaInstitute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South AfricaLaboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Estado de México, MexicoTo determine the role that the IL-4/IL13 receptor plays in the development of alternatively activated macrophages (AAM or M2) and their role in the regulation of immunity to the extraintestinal phase of the helminth parasite <i>Taenia crassiceps</i>, we followed the infection in a mouse strain lacking the IL-4Rα gene (IL-4Rα<sup>−/−</sup>) and in the macrophage/neutrophil-specific IL-4Rα-deficient mouse strain (LysMcreIL-4Rα<sup>−/lox</sup> or cre/LoxP). While 100% of <i>T. crassiceps</i>-infected IL-4Rα<sup>+/+</sup> (WT) mice harbored large parasite loads, more than 50% of th eIL-4Rα<sup>−/−</sup> mice resolved the infection. Approximately 88% of the LysMcreIL-4Rα<sup>−/lox</sup> mice displayed a sterilizing immunity to the infection. The remaining few infected cre/LoxP mice displayed the lowest number of larvae in their peritoneal cavity. The inability of the WT mice to control the infection was associated with antigen-specific Th2-type responses with higher levels of IgG1, IL-4, IL-13, and total IgE, reduced NO production, and increased arginase activity. In contrast, IL-4Rα<sup>−/−</sup> semi-resistant mice showed a Th1/Th2 combined response. Furthermore, macrophages from the WT mice displayed higher transcripts for Arginase-1 and RELM-α, as well as increased expression of PD-L2 with robust suppressive activity over anti-CD3/CD28 stimulated T cells; all of these features are associated with the AAM or M2 macrophage phenotype. In contrast, both the IL-4Rα<sup>−/−</sup> and LysMcreIL-4Rα<sup>−/lox</sup> mice did not fully develop AAM or display suppressive activity over CD3/CD28 stimulated T cells, reducing PDL2 expression. Additionally, T-CD8<sup>+</sup> but no T-CD4<sup>+</sup> cells showed a suppressive phenotype with increased Tim-3 and PD1 expression in WT and IL-4Rα<sup>−/−</sup>, which were absent in <i>T. crassiceps</i>-infected LysMcreIL-4Rα<sup>−/lox</sup> mice. These findings demonstrate a critical role for the IL-4 signaling pathway in sustaining AAM and its suppressive activity during cysticercosis, suggesting a pivotal role for AAM in favoring susceptibility to <i>T. crassiceps</i> infection. Thus, the absence of these suppressor cells is one of the leading mechanisms to control experimental cysticercosis successfully.https://www.mdpi.com/2076-0817/13/2/169helminth infectionalternatively activated macrophages<i>Taenia crassiceps</i> |
| spellingShingle | Jonadab E. Olguín Edmundo Corano-Arredondo Victoria Hernández-Gómez Irma Rivera-Montoya Mario A. Rodríguez Itzel Medina-Andrade Berenice Arendse Frank Brombacher Luis I. Terrazas A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis Pathogens helminth infection alternatively activated macrophages <i>Taenia crassiceps</i> |
| title | A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis |
| title_full | A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis |
| title_fullStr | A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis |
| title_full_unstemmed | A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis |
| title_short | A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis |
| title_sort | myeloid specific lack of il 4rα prevents the development of alternatively activated macrophages and enhances immunity to experimental cysticercosis |
| topic | helminth infection alternatively activated macrophages <i>Taenia crassiceps</i> |
| url | https://www.mdpi.com/2076-0817/13/2/169 |
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