Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles
The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowe...
Gespeichert in:
Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-08, Vol.115 (33), p.8418-8423 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 8423 |
---|---|
container_issue | 33 |
container_start_page | 8418 |
container_title | Proceedings of the National Academy of Sciences - PNAS |
container_volume | 115 |
creator | Kayama, Hisako Kohyama, Masako Okuzaki, Daisuke Motooka, Daisuke Barman, Soumik Okumura, Ryu Muneta, Masato Hoshino, Katsuaki Sasaki, Izumi Ise, Wataru Matsuno, Hiroshi Nishimura, Junichi Kurosaki, Tomohiro Nakamura, Shota Arase, Hisashi Kaisho, Tsuneyasu Takeda, Kiyoshi |
description | The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CX₃CR1high Mϕs. Intestinal CX₃CR1high Mϕs highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spicflox/flox
) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CX₃CR1high Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox
mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the non-inflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5. |
doi_str_mv | 10.1073/pnas.1808426115 |
format | Article |
fullrecord | <record><control><sourceid>jstor_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6099887</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>26530253</jstor_id><sourcerecordid>26530253</sourcerecordid><originalsourceid>FETCH-LOGICAL-c443t-9b6ec9d8b76ec9afb7179fa1014ba374f204be6ea5f46f7995a9628cfdafb23d3</originalsourceid><addsrcrecordid>eNpdkc2P1SAUxYnROM_RtSsNiRs3nbm0FMrGxEzUMZnEja4JLfDKC4UK7Yyz8W-X5o3Pj9VNOL97wrkHoZcELgjw5nIOKl-QDjpaM0LaR2hHQJCKUQGP0Q6g5lWR6Bl6lvMBAETbwVN01gAwQkm7Qz-vzWSwmox3ManFZKzNjyWpgHPUbp1wXr0t75ULeh2MxkP0bnEZL2OK637Ec4q3Truwxy6U9cUF5fGkhhTnUe2L351bRhxicMF6NU1qiel-27LOm_wcPbHKZ_PiYZ6jbx8_fL26rm6-fPp89f6mGihtlkr0zAxCdz3fprI9J1xYRYDQXjWc2hpob5hRraXMciFaJVjdDVYXtm50c47eHX3ntZ-MHkwoGb2ck5tUupdROfmvEtwo9_FWMhCi63gxePtgkOL3teSUk8uD8V4FE9csa9hKoLTd0Df_oYe4pnKWjRJc8NIQKdTlkSqXyjkZe_oMAbl1K7du5Z9uy8brvzOc-N9lFuDVETjkcuSTXrO2gbptml_KDq9C</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2097970911</pqid></control><display><type>article</type><title>Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles</title><source>MEDLINE</source><source>Jstor Complete Legacy</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Kayama, Hisako ; Kohyama, Masako ; Okuzaki, Daisuke ; Motooka, Daisuke ; Barman, Soumik ; Okumura, Ryu ; Muneta, Masato ; Hoshino, Katsuaki ; Sasaki, Izumi ; Ise, Wataru ; Matsuno, Hiroshi ; Nishimura, Junichi ; Kurosaki, Tomohiro ; Nakamura, Shota ; Arase, Hisashi ; Kaisho, Tsuneyasu ; Takeda, Kiyoshi</creator><creatorcontrib>Kayama, Hisako ; Kohyama, Masako ; Okuzaki, Daisuke ; Motooka, Daisuke ; Barman, Soumik ; Okumura, Ryu ; Muneta, Masato ; Hoshino, Katsuaki ; Sasaki, Izumi ; Ise, Wataru ; Matsuno, Hiroshi ; Nishimura, Junichi ; Kurosaki, Tomohiro ; Nakamura, Shota ; Arase, Hisashi ; Kaisho, Tsuneyasu ; Takeda, Kiyoshi</creatorcontrib><description>The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CX₃CR1high Mϕs. Intestinal CX₃CR1high Mϕs highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spicflox/flox
) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CX₃CR1high Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox
mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the non-inflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1808426115</identifier><identifier>PMID: 30061415</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Bleeding ; Colitis ; Colitis - drug therapy ; Complex formation ; CX3C Chemokine Receptor 1 - physiology ; Cytokines - biosynthesis ; Dextran ; Dextran Sulfate - toxicity ; DNA-Binding Proteins - physiology ; Flox ; Gene expression ; Genes ; Helper cells ; Heme ; Heme - pharmacology ; Hemoglobin ; Hemorrhage ; Homeostasis ; Immune system ; Inflammation ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Interleukin 1 ; Interleukin 10 ; Interleukin 6 ; Intestine ; Intestines - immunology ; Iron, Dietary - administration & dosage ; Lipopolysaccharides ; Lymphocytes T ; Macrophages ; Macrophages - immunology ; Mice ; Mice, Inbred C57BL ; Mucosa ; NF-κB protein ; Pathogens ; Proteins ; Sodium ; Sodium sulfate ; Sulfates ; Toll-like receptors ; Toll-Like Receptors - physiology ; Transcription Factor RelA - physiology ; Tumor necrosis factor-α</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-08, Vol.115 (33), p.8418-8423</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright © 2018 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Aug 14, 2018</rights><rights>Copyright © 2018 the Author(s). Published by PNAS. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-9b6ec9d8b76ec9afb7179fa1014ba374f204be6ea5f46f7995a9628cfdafb23d3</citedby><cites>FETCH-LOGICAL-c443t-9b6ec9d8b76ec9afb7179fa1014ba374f204be6ea5f46f7995a9628cfdafb23d3</cites><orcidid>0000-0002-1153-3166 ; 0000-0003-0493-4815</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26530253$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26530253$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53769,53771,57995,58228</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30061415$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kayama, Hisako</creatorcontrib><creatorcontrib>Kohyama, Masako</creatorcontrib><creatorcontrib>Okuzaki, Daisuke</creatorcontrib><creatorcontrib>Motooka, Daisuke</creatorcontrib><creatorcontrib>Barman, Soumik</creatorcontrib><creatorcontrib>Okumura, Ryu</creatorcontrib><creatorcontrib>Muneta, Masato</creatorcontrib><creatorcontrib>Hoshino, Katsuaki</creatorcontrib><creatorcontrib>Sasaki, Izumi</creatorcontrib><creatorcontrib>Ise, Wataru</creatorcontrib><creatorcontrib>Matsuno, Hiroshi</creatorcontrib><creatorcontrib>Nishimura, Junichi</creatorcontrib><creatorcontrib>Kurosaki, Tomohiro</creatorcontrib><creatorcontrib>Nakamura, Shota</creatorcontrib><creatorcontrib>Arase, Hisashi</creatorcontrib><creatorcontrib>Kaisho, Tsuneyasu</creatorcontrib><creatorcontrib>Takeda, Kiyoshi</creatorcontrib><title>Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CX₃CR1high Mϕs. Intestinal CX₃CR1high Mϕs highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spicflox/flox
) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CX₃CR1high Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox
mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the non-inflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Bleeding</subject><subject>Colitis</subject><subject>Colitis - drug therapy</subject><subject>Complex formation</subject><subject>CX3C Chemokine Receptor 1 - physiology</subject><subject>Cytokines - biosynthesis</subject><subject>Dextran</subject><subject>Dextran Sulfate - toxicity</subject><subject>DNA-Binding Proteins - physiology</subject><subject>Flox</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Helper cells</subject><subject>Heme</subject><subject>Heme - pharmacology</subject><subject>Hemoglobin</subject><subject>Hemorrhage</subject><subject>Homeostasis</subject><subject>Immune system</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Inflammatory bowel diseases</subject><subject>Interleukin 1</subject><subject>Interleukin 10</subject><subject>Interleukin 6</subject><subject>Intestine</subject><subject>Intestines - immunology</subject><subject>Iron, Dietary - administration & dosage</subject><subject>Lipopolysaccharides</subject><subject>Lymphocytes T</subject><subject>Macrophages</subject><subject>Macrophages - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mucosa</subject><subject>NF-κB protein</subject><subject>Pathogens</subject><subject>Proteins</subject><subject>Sodium</subject><subject>Sodium sulfate</subject><subject>Sulfates</subject><subject>Toll-like receptors</subject><subject>Toll-Like Receptors - physiology</subject><subject>Transcription Factor RelA - physiology</subject><subject>Tumor necrosis factor-α</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc2P1SAUxYnROM_RtSsNiRs3nbm0FMrGxEzUMZnEja4JLfDKC4UK7Yyz8W-X5o3Pj9VNOL97wrkHoZcELgjw5nIOKl-QDjpaM0LaR2hHQJCKUQGP0Q6g5lWR6Bl6lvMBAETbwVN01gAwQkm7Qz-vzWSwmox3ManFZKzNjyWpgHPUbp1wXr0t75ULeh2MxkP0bnEZL2OK637Ec4q3Truwxy6U9cUF5fGkhhTnUe2L351bRhxicMF6NU1qiel-27LOm_wcPbHKZ_PiYZ6jbx8_fL26rm6-fPp89f6mGihtlkr0zAxCdz3fprI9J1xYRYDQXjWc2hpob5hRraXMciFaJVjdDVYXtm50c47eHX3ntZ-MHkwoGb2ck5tUupdROfmvEtwo9_FWMhCi63gxePtgkOL3teSUk8uD8V4FE9csa9hKoLTd0Df_oYe4pnKWjRJc8NIQKdTlkSqXyjkZe_oMAbl1K7du5Z9uy8brvzOc-N9lFuDVETjkcuSTXrO2gbptml_KDq9C</recordid><startdate>20180814</startdate><enddate>20180814</enddate><creator>Kayama, Hisako</creator><creator>Kohyama, Masako</creator><creator>Okuzaki, Daisuke</creator><creator>Motooka, Daisuke</creator><creator>Barman, Soumik</creator><creator>Okumura, Ryu</creator><creator>Muneta, Masato</creator><creator>Hoshino, Katsuaki</creator><creator>Sasaki, Izumi</creator><creator>Ise, Wataru</creator><creator>Matsuno, Hiroshi</creator><creator>Nishimura, Junichi</creator><creator>Kurosaki, Tomohiro</creator><creator>Nakamura, Shota</creator><creator>Arase, Hisashi</creator><creator>Kaisho, Tsuneyasu</creator><creator>Takeda, Kiyoshi</creator><general>National Academy of Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1153-3166</orcidid><orcidid>https://orcid.org/0000-0003-0493-4815</orcidid></search><sort><creationdate>20180814</creationdate><title>Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles</title><author>Kayama, Hisako ; Kohyama, Masako ; Okuzaki, Daisuke ; Motooka, Daisuke ; Barman, Soumik ; Okumura, Ryu ; Muneta, Masato ; Hoshino, Katsuaki ; Sasaki, Izumi ; Ise, Wataru ; Matsuno, Hiroshi ; Nishimura, Junichi ; Kurosaki, Tomohiro ; Nakamura, Shota ; Arase, Hisashi ; Kaisho, Tsuneyasu ; Takeda, Kiyoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-9b6ec9d8b76ec9afb7179fa1014ba374f204be6ea5f46f7995a9628cfdafb23d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Biological Sciences</topic><topic>Bleeding</topic><topic>Colitis</topic><topic>Colitis - drug therapy</topic><topic>Complex formation</topic><topic>CX3C Chemokine Receptor 1 - physiology</topic><topic>Cytokines - biosynthesis</topic><topic>Dextran</topic><topic>Dextran Sulfate - toxicity</topic><topic>DNA-Binding Proteins - physiology</topic><topic>Flox</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Helper cells</topic><topic>Heme</topic><topic>Heme - pharmacology</topic><topic>Hemoglobin</topic><topic>Hemorrhage</topic><topic>Homeostasis</topic><topic>Immune system</topic><topic>Inflammation</topic><topic>Inflammatory bowel disease</topic><topic>Inflammatory bowel diseases</topic><topic>Interleukin 1</topic><topic>Interleukin 10</topic><topic>Interleukin 6</topic><topic>Intestine</topic><topic>Intestines - immunology</topic><topic>Iron, Dietary - administration & dosage</topic><topic>Lipopolysaccharides</topic><topic>Lymphocytes T</topic><topic>Macrophages</topic><topic>Macrophages - immunology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mucosa</topic><topic>NF-κB protein</topic><topic>Pathogens</topic><topic>Proteins</topic><topic>Sodium</topic><topic>Sodium sulfate</topic><topic>Sulfates</topic><topic>Toll-like receptors</topic><topic>Toll-Like Receptors - physiology</topic><topic>Transcription Factor RelA - physiology</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kayama, Hisako</creatorcontrib><creatorcontrib>Kohyama, Masako</creatorcontrib><creatorcontrib>Okuzaki, Daisuke</creatorcontrib><creatorcontrib>Motooka, Daisuke</creatorcontrib><creatorcontrib>Barman, Soumik</creatorcontrib><creatorcontrib>Okumura, Ryu</creatorcontrib><creatorcontrib>Muneta, Masato</creatorcontrib><creatorcontrib>Hoshino, Katsuaki</creatorcontrib><creatorcontrib>Sasaki, Izumi</creatorcontrib><creatorcontrib>Ise, Wataru</creatorcontrib><creatorcontrib>Matsuno, Hiroshi</creatorcontrib><creatorcontrib>Nishimura, Junichi</creatorcontrib><creatorcontrib>Kurosaki, Tomohiro</creatorcontrib><creatorcontrib>Nakamura, Shota</creatorcontrib><creatorcontrib>Arase, Hisashi</creatorcontrib><creatorcontrib>Kaisho, Tsuneyasu</creatorcontrib><creatorcontrib>Takeda, Kiyoshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kayama, Hisako</au><au>Kohyama, Masako</au><au>Okuzaki, Daisuke</au><au>Motooka, Daisuke</au><au>Barman, Soumik</au><au>Okumura, Ryu</au><au>Muneta, Masato</au><au>Hoshino, Katsuaki</au><au>Sasaki, Izumi</au><au>Ise, Wataru</au><au>Matsuno, Hiroshi</au><au>Nishimura, Junichi</au><au>Kurosaki, Tomohiro</au><au>Nakamura, Shota</au><au>Arase, Hisashi</au><au>Kaisho, Tsuneyasu</au><au>Takeda, Kiyoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2018-08-14</date><risdate>2018</risdate><volume>115</volume><issue>33</issue><spage>8418</spage><epage>8423</epage><pages>8418-8423</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CX₃CR1high Mϕs. Intestinal CX₃CR1high Mϕs highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spicflox/flox
) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CX₃CR1high Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox
mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the non-inflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30061415</pmid><doi>10.1073/pnas.1808426115</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-1153-3166</orcidid><orcidid>https://orcid.org/0000-0003-0493-4815</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0027-8424 |
ispartof | Proceedings of the National Academy of Sciences - PNAS, 2018-08, Vol.115 (33), p.8418-8423 |
issn | 0027-8424 1091-6490 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6099887 |
source | MEDLINE; Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
subjects | Animals Biological Sciences Bleeding Colitis Colitis - drug therapy Complex formation CX3C Chemokine Receptor 1 - physiology Cytokines - biosynthesis Dextran Dextran Sulfate - toxicity DNA-Binding Proteins - physiology Flox Gene expression Genes Helper cells Heme Heme - pharmacology Hemoglobin Hemorrhage Homeostasis Immune system Inflammation Inflammatory bowel disease Inflammatory bowel diseases Interleukin 1 Interleukin 10 Interleukin 6 Intestine Intestines - immunology Iron, Dietary - administration & dosage Lipopolysaccharides Lymphocytes T Macrophages Macrophages - immunology Mice Mice, Inbred C57BL Mucosa NF-κB protein Pathogens Proteins Sodium Sodium sulfate Sulfates Toll-like receptors Toll-Like Receptors - physiology Transcription Factor RelA - physiology Tumor necrosis factor-α |
title | Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T04%3A58%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Heme%20ameliorates%20dextran%20sodium%20sulfate-induced%20colitis%20through%20providing%20intestinal%20macrophages%20with%20noninflammatory%20profiles&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Kayama,%20Hisako&rft.date=2018-08-14&rft.volume=115&rft.issue=33&rft.spage=8418&rft.epage=8423&rft.pages=8418-8423&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1808426115&rft_dat=%3Cjstor_pubme%3E26530253%3C/jstor_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2097970911&rft_id=info:pmid/30061415&rft_jstor_id=26530253&rfr_iscdi=true |