Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophages
IL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory arthritis (ICI-arthritis), and pancreatic cancer and proposed to be pathogenic. IL-1β+ macrophages express genes cooperatively induced by PGE2 and TNF signaling, but mechan...
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eLife Sciences Publications Ltd
2025-07-01
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| Online Access: | https://elifesciences.org/articles/104367 |
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| author | Upneet K Sokhi Ruoxi Yuan Bikash Mishra Yurii Chinenov Anvita Singaraju Karmela K Chan Anne Bass Richard D Bell Laura Donlin Lionel B Ivashkiv |
| author_facet | Upneet K Sokhi Ruoxi Yuan Bikash Mishra Yurii Chinenov Anvita Singaraju Karmela K Chan Anne Bass Richard D Bell Laura Donlin Lionel B Ivashkiv |
| author_sort | Upneet K Sokhi |
| collection | DOAJ |
| description | IL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory arthritis (ICI-arthritis), and pancreatic cancer and proposed to be pathogenic. IL-1β+ macrophages express genes cooperatively induced by PGE2 and TNF signaling, but mechanisms that induce these cells are not known. We used an integrated transcriptomic and epigenomic analysis in primary human monocytes to study PGE2-TNF crosstalk, and how it is regulated by IFN-γ, as occurs in RA synovial macrophages. We identified a TNF + PGE2 (TP) induced gene expression signature that is enriched in IL1β+ RA and ICI-arthritis monocytic subsets, and includes genes in pathogenic IL-1, Notch and neutrophil chemokine pathways. ICI-arthritis myeloid cells mapped primarily onto four previously defined RA synovial monocytic clusters, and TP genes were expressed in a manner suggestive of a new functional monocyte subset. TP signature genes are distinct from canonical inflammatory NF-κB target genes such as TNF, IL6 and IL12B and are activated by cooperation of PGE2-induced AP-1, CEBP and NR4A family transcription factors with TNF-induced NF-κB activity. Unexpectedly, IFN-γ suppressed induction of AP-1, CEBP and NR4A activity to ablate induction of IL-1, Notch and neutrophil chemokine genes, while promoting expression of distinct inflammatory genes such as TNF and T cell chemokines like CXCL10. The opposing cross-regulation of PGE2 and IFN signaling in vitro was reflected in vivo in mutually exclusive expression of TP and IFN signatures in different cell clusters in RA and ICI-arthritis monocytes. These results reveal the basis for synergistic induction of inflammatory genes by PGE2 and TNF, and a novel regulatory axis whereby IFN-γ and PGE2 oppose each other to determine the balance between two distinct TNF-induced inflammatory gene expression programs relevant for RA and ICI-arthritis. |
| format | Article |
| id | doaj-art-cf89eecf8cd645368d1c5b5d1f8f1f08 |
| institution | Matheson Library |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-cf89eecf8cd645368d1c5b5d1f8f1f082025-07-15T13:43:38ZengeLife Sciences Publications LtdeLife2050-084X2025-07-011410.7554/eLife.104367Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophagesUpneet K Sokhi0https://orcid.org/0000-0001-5907-5646Ruoxi Yuan1Bikash Mishra2Yurii Chinenov3Anvita Singaraju4Karmela K Chan5Anne Bass6Richard D Bell7Laura Donlin8Lionel B Ivashkiv9https://orcid.org/0000-0002-9951-0646HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United StatesHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States; Computational Biology Core, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United StatesHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, United StatesHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States; Computational Biology Core, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United StatesHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, United StatesDivision of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, United States; Department of Medicine, Weill Cornell Medicine, New York, United StatesDivision of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, United States; Department of Medicine, Weill Cornell Medicine, New York, United StatesHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States; Computational Biology Core, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, United StatesHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, United States; Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, United States; Department of Medicine, Weill Cornell Medicine, New York, United StatesHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, United States; Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, United States; Department of Medicine, Weill Cornell Medicine, New York, United StatesIL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory arthritis (ICI-arthritis), and pancreatic cancer and proposed to be pathogenic. IL-1β+ macrophages express genes cooperatively induced by PGE2 and TNF signaling, but mechanisms that induce these cells are not known. We used an integrated transcriptomic and epigenomic analysis in primary human monocytes to study PGE2-TNF crosstalk, and how it is regulated by IFN-γ, as occurs in RA synovial macrophages. We identified a TNF + PGE2 (TP) induced gene expression signature that is enriched in IL1β+ RA and ICI-arthritis monocytic subsets, and includes genes in pathogenic IL-1, Notch and neutrophil chemokine pathways. ICI-arthritis myeloid cells mapped primarily onto four previously defined RA synovial monocytic clusters, and TP genes were expressed in a manner suggestive of a new functional monocyte subset. TP signature genes are distinct from canonical inflammatory NF-κB target genes such as TNF, IL6 and IL12B and are activated by cooperation of PGE2-induced AP-1, CEBP and NR4A family transcription factors with TNF-induced NF-κB activity. Unexpectedly, IFN-γ suppressed induction of AP-1, CEBP and NR4A activity to ablate induction of IL-1, Notch and neutrophil chemokine genes, while promoting expression of distinct inflammatory genes such as TNF and T cell chemokines like CXCL10. The opposing cross-regulation of PGE2 and IFN signaling in vitro was reflected in vivo in mutually exclusive expression of TP and IFN signatures in different cell clusters in RA and ICI-arthritis monocytes. These results reveal the basis for synergistic induction of inflammatory genes by PGE2 and TNF, and a novel regulatory axis whereby IFN-γ and PGE2 oppose each other to determine the balance between two distinct TNF-induced inflammatory gene expression programs relevant for RA and ICI-arthritis.https://elifesciences.org/articles/104367macrophagesinflammationtumor necrosis factorinterferon gammaimmune checkpoint inhibitionrheumatoid arthritis |
| spellingShingle | Upneet K Sokhi Ruoxi Yuan Bikash Mishra Yurii Chinenov Anvita Singaraju Karmela K Chan Anne Bass Richard D Bell Laura Donlin Lionel B Ivashkiv Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophages eLife macrophages inflammation tumor necrosis factor interferon gamma immune checkpoint inhibition rheumatoid arthritis |
| title | Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophages |
| title_full | Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophages |
| title_fullStr | Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophages |
| title_full_unstemmed | Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophages |
| title_short | Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophages |
| title_sort | opposing regulation of tnf responses by ifn γ and a pge2 camp axis that is apparent in rheumatoid and immune checkpoint inhibitor induced arthritis human il 1β macrophages |
| topic | macrophages inflammation tumor necrosis factor interferon gamma immune checkpoint inhibition rheumatoid arthritis |
| url | https://elifesciences.org/articles/104367 |
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