CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis
Intercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.159469 |
| _version_ | 1797634347429265408 |
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| author | Kaylyn M. Bauer Morgan C. Nelson William W. Tang Tyson R. Chiaro D. Garrett Brown Arevik Ghazaryan Soh-Hyun Lee Allison M. Weis Jennifer H. Hill Kendra A. Klag Van B. Tran Jacob W. Thompson Andrew G. Ramstead Josh K. Monts James E. Marvin Margaret Alexander Warren P. Voth W. Zac Stephens Diane M. Ward Aaron C. Petrey June L. Round Ryan M. O’Connell |
| author_facet | Kaylyn M. Bauer Morgan C. Nelson William W. Tang Tyson R. Chiaro D. Garrett Brown Arevik Ghazaryan Soh-Hyun Lee Allison M. Weis Jennifer H. Hill Kendra A. Klag Van B. Tran Jacob W. Thompson Andrew G. Ramstead Josh K. Monts James E. Marvin Margaret Alexander Warren P. Voth W. Zac Stephens Diane M. Ward Aaron C. Petrey June L. Round Ryan M. O’Connell |
| author_sort | Kaylyn M. Bauer |
| collection | DOAJ |
| description | Intercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and inflammation are largely uncharacterized. By generating mouse strains deficient in cell-specific exosome production, we demonstrate deletion of the small GTPase Rab27A in CD11c+ cells exacerbated murine colitis, which was reversible through administration of DC-derived exosomes. Profiling RNAs within colon exosomes revealed a distinct subset of miRNAs carried by colon- and DC-derived exosomes. Among antiinflammatory exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages. Further, we have identified a potentially novel mode of exosome-mediated DC and macrophage crosstalk that is capable of skewing gut macrophages toward an antiinflammatory phenotype. Assessing clinical samples, RAB27A, select miRNAs, and RNA-binding proteins that load exosomal miRNAs were dysregulated in ulcerative colitis patient samples, consistent with our preclinical mouse model findings. Together, our work reveals an exosome-mediated regulatory mechanism underlying gut inflammation and paves the way for potential use of miRNA-containing exosomes as a novel therapeutic for inflammatory bowel disease. |
| first_indexed | 2024-03-11T12:07:21Z |
| format | Article |
| id | doaj.art-28e27534285f41e8b7743abd9a89a3a7 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:21Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-28e27534285f41e8b7743abd9a89a3a72023-11-07T16:24:39ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-10-01719CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitisKaylyn M. BauerMorgan C. NelsonWilliam W. TangTyson R. ChiaroD. Garrett BrownArevik GhazaryanSoh-Hyun LeeAllison M. WeisJennifer H. HillKendra A. KlagVan B. TranJacob W. ThompsonAndrew G. RamsteadJosh K. MontsJames E. MarvinMargaret AlexanderWarren P. VothW. Zac StephensDiane M. WardAaron C. PetreyJune L. RoundRyan M. O’ConnellIntercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and inflammation are largely uncharacterized. By generating mouse strains deficient in cell-specific exosome production, we demonstrate deletion of the small GTPase Rab27A in CD11c+ cells exacerbated murine colitis, which was reversible through administration of DC-derived exosomes. Profiling RNAs within colon exosomes revealed a distinct subset of miRNAs carried by colon- and DC-derived exosomes. Among antiinflammatory exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages. Further, we have identified a potentially novel mode of exosome-mediated DC and macrophage crosstalk that is capable of skewing gut macrophages toward an antiinflammatory phenotype. Assessing clinical samples, RAB27A, select miRNAs, and RNA-binding proteins that load exosomal miRNAs were dysregulated in ulcerative colitis patient samples, consistent with our preclinical mouse model findings. Together, our work reveals an exosome-mediated regulatory mechanism underlying gut inflammation and paves the way for potential use of miRNA-containing exosomes as a novel therapeutic for inflammatory bowel disease.https://doi.org/10.1172/jci.insight.159469Cell biologyImmunology |
| spellingShingle | Kaylyn M. Bauer Morgan C. Nelson William W. Tang Tyson R. Chiaro D. Garrett Brown Arevik Ghazaryan Soh-Hyun Lee Allison M. Weis Jennifer H. Hill Kendra A. Klag Van B. Tran Jacob W. Thompson Andrew G. Ramstead Josh K. Monts James E. Marvin Margaret Alexander Warren P. Voth W. Zac Stephens Diane M. Ward Aaron C. Petrey June L. Round Ryan M. O’Connell CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis JCI Insight Cell biology Immunology |
| title | CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis |
| title_full | CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis |
| title_fullStr | CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis |
| title_full_unstemmed | CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis |
| title_short | CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis |
| title_sort | cd11c myeloid cell exosomes reduce intestinal inflammation during colitis |
| topic | Cell biology Immunology |
| url | https://doi.org/10.1172/jci.insight.159469 |
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