Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum
Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum because granulomas induced by this pathogenic fu...
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Veröffentlicht in: | The Journal of immunology (1950) 2016-07, Vol.197 (2), p.565-579 |
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description | Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum because granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. In this study, we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to 7 d postinfection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕs) constituted most IL-10-producing cells. Deletion of HIF-1α in neutrophils or dendritic cells did not alter fungal burden, thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕs following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕs by IFN-γ and effective handling of H. capsulatum. |
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We investigated the function of HIF-1α in the host response to Histoplasma capsulatum because granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. In this study, we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to 7 d postinfection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕs) constituted most IL-10-producing cells. Deletion of HIF-1α in neutrophils or dendritic cells did not alter fungal burden, thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕs following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕs by IFN-γ and effective handling of H. capsulatum.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1600342</identifier><identifier>PMID: 27271565</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Blotting, Western ; CREB-Binding Protein - immunology ; Disease Models, Animal ; Flow Cytometry ; Histoplasma - immunology ; Histoplasma capsulatum ; Histoplasmosis - immunology ; Hypoxia-Inducible Factor 1, alpha Subunit - immunology ; Interleukin-10 - immunology ; Macrophages - immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Confocal ; Real-Time Polymerase Chain Reaction</subject><ispartof>The Journal of immunology (1950), 2016-07, Vol.197 (2), p.565-579</ispartof><rights>Copyright © 2016 by The American Association of Immunologists, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c359t-fc4c0ece79f0435d5b3c9ef2c73ed90a2f56378ae42fa435443edbe33d57edec3</citedby><cites>FETCH-LOGICAL-c359t-fc4c0ece79f0435d5b3c9ef2c73ed90a2f56378ae42fa435443edbe33d57edec3</cites><orcidid>0000-0001-7565-7216 ; 0000-0001-8812-489X ; 0000-0001-6158-6461</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27271565$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fecher, Roger A</creatorcontrib><creatorcontrib>Horwath, Michael C</creatorcontrib><creatorcontrib>Friedrich, Dirk</creatorcontrib><creatorcontrib>Rupp, Jan</creatorcontrib><creatorcontrib>Deepe, Jr, George S</creatorcontrib><title>Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum because granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. In this study, we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to 7 d postinfection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕs) constituted most IL-10-producing cells. Deletion of HIF-1α in neutrophils or dendritic cells did not alter fungal burden, thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕs following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕs by IFN-γ and effective handling of H. capsulatum.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>CREB-Binding Protein - immunology</subject><subject>Disease Models, Animal</subject><subject>Flow Cytometry</subject><subject>Histoplasma - immunology</subject><subject>Histoplasma capsulatum</subject><subject>Histoplasmosis - immunology</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - immunology</subject><subject>Interleukin-10 - immunology</subject><subject>Macrophages - immunology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Microscopy, Confocal</subject><subject>Real-Time Polymerase Chain Reaction</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc9u1DAQxi1ERZeFOyfkI5eU8f_1BQmtKBtpUS9wtrzOpJsqsYOdtOKx-iJ9JoK6reDGaaSZb36abz5C3jG4kCDtx5tuGOaY-gumAYTkL8iKKQWV1qBfkhUA5xUz2pyT16XcAIAGLl-Rc264YUqrFfF1vMVckG5Tztj7qUuRHnC6Q4y03lcMqI8N3dWXFXu4p12k33zIaTz6ayy0ji2GCRt6101HuuvKlMbel8HT4McyL7h5eEPOWt8XfHuqa_Lj8sv37a7aX32tt5_3VRDKTlUbZAAMaGwLUqhGHUSw2PJgBDYWPG-VFmbjUfLWLwIpl_4BhWiUwQaDWJNPj9xxPgzYBIxT9r0bczf4_Msl37l_J7E7uut066QVSku-AD6cADn9nLFMbuhKwL73EdNcHNvARlutN_Z_pFxqaxYnawKP0uVrpWRsny9i4P6E6J5CdKcQl5X3fzt5XnhKTfwG6-qcjQ</recordid><startdate>20160715</startdate><enddate>20160715</enddate><creator>Fecher, Roger A</creator><creator>Horwath, Michael C</creator><creator>Friedrich, Dirk</creator><creator>Rupp, Jan</creator><creator>Deepe, Jr, George S</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>M7N</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7565-7216</orcidid><orcidid>https://orcid.org/0000-0001-8812-489X</orcidid><orcidid>https://orcid.org/0000-0001-6158-6461</orcidid></search><sort><creationdate>20160715</creationdate><title>Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum</title><author>Fecher, Roger A ; Horwath, Michael C ; Friedrich, Dirk ; Rupp, Jan ; Deepe, Jr, George S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c359t-fc4c0ece79f0435d5b3c9ef2c73ed90a2f56378ae42fa435443edbe33d57edec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Blotting, Western</topic><topic>CREB-Binding Protein - immunology</topic><topic>Disease Models, Animal</topic><topic>Flow Cytometry</topic><topic>Histoplasma - immunology</topic><topic>Histoplasma capsulatum</topic><topic>Histoplasmosis - immunology</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - immunology</topic><topic>Interleukin-10 - immunology</topic><topic>Macrophages - immunology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Microscopy, Confocal</topic><topic>Real-Time Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fecher, Roger A</creatorcontrib><creatorcontrib>Horwath, Michael C</creatorcontrib><creatorcontrib>Friedrich, Dirk</creatorcontrib><creatorcontrib>Rupp, Jan</creatorcontrib><creatorcontrib>Deepe, Jr, George S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fecher, Roger A</au><au>Horwath, Michael C</au><au>Friedrich, Dirk</au><au>Rupp, Jan</au><au>Deepe, Jr, George S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2016-07-15</date><risdate>2016</risdate><volume>197</volume><issue>2</issue><spage>565</spage><epage>579</epage><pages>565-579</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum because granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. In this study, we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to 7 d postinfection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕs) constituted most IL-10-producing cells. Deletion of HIF-1α in neutrophils or dendritic cells did not alter fungal burden, thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕs following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕs by IFN-γ and effective handling of H. capsulatum.</abstract><cop>United States</cop><pmid>27271565</pmid><doi>10.4049/jimmunol.1600342</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-7565-7216</orcidid><orcidid>https://orcid.org/0000-0001-8812-489X</orcidid><orcidid>https://orcid.org/0000-0001-6158-6461</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Blotting, Western CREB-Binding Protein - immunology Disease Models, Animal Flow Cytometry Histoplasma - immunology Histoplasma capsulatum Histoplasmosis - immunology Hypoxia-Inducible Factor 1, alpha Subunit - immunology Interleukin-10 - immunology Macrophages - immunology Male Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Confocal Real-Time Polymerase Chain Reaction |
title | Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum |
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