Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus
We describe a mechanism responsible for systemic lupus erythematosus (SLE). In humans with SLE and in 2 SLE murine models, there was marked enrichment of isolevuglandin-adducted proteins (isoLG adducts) in monocytes and dendritic cells. We found that antibodies formed against isoLG adducts in both S...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-07-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.136678 |
| _version_ | 1811334850014085120 |
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| author | David M. Patrick Néstor de la Visitación Jaya Krishnan Wei Chen Michelle J. Ormseth C. Michael Stein Sean S. Davies Venkataraman Amarnath Leslie J. Crofford Jonathan M. Williams Shilin Zhao Charles D. Smart Sergey Dikalov Anna Dikalova Liang Xiao Justin P. Van Beusecum Mingfang Ao Agnes B. Fogo Annet Kirabo David G. Harrison |
| author_facet | David M. Patrick Néstor de la Visitación Jaya Krishnan Wei Chen Michelle J. Ormseth C. Michael Stein Sean S. Davies Venkataraman Amarnath Leslie J. Crofford Jonathan M. Williams Shilin Zhao Charles D. Smart Sergey Dikalov Anna Dikalova Liang Xiao Justin P. Van Beusecum Mingfang Ao Agnes B. Fogo Annet Kirabo David G. Harrison |
| author_sort | David M. Patrick |
| collection | DOAJ |
| description | We describe a mechanism responsible for systemic lupus erythematosus (SLE). In humans with SLE and in 2 SLE murine models, there was marked enrichment of isolevuglandin-adducted proteins (isoLG adducts) in monocytes and dendritic cells. We found that antibodies formed against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduced transcription of all C1q subunits. Treatment of SLE-prone mice with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) ameliorated parameters of autoimmunity, including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowered blood pressure, attenuated renal injury, and reduced inflammatory gene expression uniquely in C1q-expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE. |
| first_indexed | 2024-04-13T17:15:26Z |
| format | Article |
| id | doaj.art-0ffb535cc4884c4e8239a5a73b588dd4 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T17:15:26Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-0ffb535cc4884c4e8239a5a73b588dd42022-12-22T02:38:08ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-07-01713Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosusDavid M. PatrickNéstor de la VisitaciónJaya KrishnanWei ChenMichelle J. OrmsethC. Michael SteinSean S. DaviesVenkataraman AmarnathLeslie J. CroffordJonathan M. WilliamsShilin ZhaoCharles D. SmartSergey DikalovAnna DikalovaLiang XiaoJustin P. Van BeusecumMingfang AoAgnes B. FogoAnnet KiraboDavid G. HarrisonWe describe a mechanism responsible for systemic lupus erythematosus (SLE). In humans with SLE and in 2 SLE murine models, there was marked enrichment of isolevuglandin-adducted proteins (isoLG adducts) in monocytes and dendritic cells. We found that antibodies formed against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduced transcription of all C1q subunits. Treatment of SLE-prone mice with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) ameliorated parameters of autoimmunity, including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowered blood pressure, attenuated renal injury, and reduced inflammatory gene expression uniquely in C1q-expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.https://doi.org/10.1172/jci.insight.136678AutoimmunityInflammation |
| spellingShingle | David M. Patrick Néstor de la Visitación Jaya Krishnan Wei Chen Michelle J. Ormseth C. Michael Stein Sean S. Davies Venkataraman Amarnath Leslie J. Crofford Jonathan M. Williams Shilin Zhao Charles D. Smart Sergey Dikalov Anna Dikalova Liang Xiao Justin P. Van Beusecum Mingfang Ao Agnes B. Fogo Annet Kirabo David G. Harrison Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus JCI Insight Autoimmunity Inflammation |
| title | Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus |
| title_full | Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus |
| title_fullStr | Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus |
| title_full_unstemmed | Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus |
| title_short | Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus |
| title_sort | isolevuglandins disrupt pu 1 mediated c1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus |
| topic | Autoimmunity Inflammation |
| url | https://doi.org/10.1172/jci.insight.136678 |
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