Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections
Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) i...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.698420/full |
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| author | Nadine Szumilas Odilia B. J. Corneth Christian H. K. Lehmann Christian H. K. Lehmann Christian H. K. Lehmann Heike Schmitt Svenia Cunz Jolie G. Cullen Talyn Chu Anita Marosan Attila Mócsai Vladimir Benes Dietmar Zehn Diana Dudziak Diana Dudziak Diana Dudziak Rudi W. Hendriks Lars Nitschke Lars Nitschke |
| author_facet | Nadine Szumilas Odilia B. J. Corneth Christian H. K. Lehmann Christian H. K. Lehmann Christian H. K. Lehmann Heike Schmitt Svenia Cunz Jolie G. Cullen Talyn Chu Anita Marosan Attila Mócsai Vladimir Benes Dietmar Zehn Diana Dudziak Diana Dudziak Diana Dudziak Rudi W. Hendriks Lars Nitschke Lars Nitschke |
| author_sort | Nadine Szumilas |
| collection | DOAJ |
| description | Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs. |
| first_indexed | 2024-12-18T01:11:43Z |
| format | Article |
| id | doaj.art-c505db08fdab443ead7dba66ecb91da3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-18T01:11:43Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-c505db08fdab443ead7dba66ecb91da32022-12-21T21:26:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-08-011210.3389/fimmu.2021.698420698420Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV InfectionsNadine Szumilas0Odilia B. J. Corneth1Christian H. K. Lehmann2Christian H. K. Lehmann3Christian H. K. Lehmann4Heike Schmitt5Svenia Cunz6Jolie G. Cullen7Talyn Chu8Anita Marosan9Attila Mócsai10Vladimir Benes11Dietmar Zehn12Diana Dudziak13Diana Dudziak14Diana Dudziak15Rudi W. Hendriks16Lars Nitschke17Lars Nitschke18Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, GermanyDepartment of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, NetherlandsLaboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Erlangen, GermanyDeutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, University of Erlangen-Nürnberg, Erlangen, GermanyMedical Immunology Campus Erlangen (MICE), University of Erlangen-Nürnberg, Erlangen, GermanyFirst Department of Medicine, University Hospital Erlangen, Erlangen, GermanyDivision of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, GermanyDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, GermanyDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, GermanyDepartment of Immune Modulation, University Hospital Erlangen, Erlangen, GermanySemmelweis University School of Medicine, Budapest, Hungary0Genomics Core Facility, EMBL Heidelberg, Heidelberg, GermanyDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, GermanyLaboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Erlangen, GermanyDeutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, University of Erlangen-Nürnberg, Erlangen, GermanyMedical Immunology Campus Erlangen (MICE), University of Erlangen-Nürnberg, Erlangen, GermanyDepartment of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, NetherlandsDivision of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, GermanyMedical Immunology Campus Erlangen (MICE), University of Erlangen-Nürnberg, Erlangen, GermanySiglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.https://www.frontiersin.org/articles/10.3389/fimmu.2021.698420/fullplasmacytoid dendritic cellsInterferon-alphaSiglecTLR9SLE |
| spellingShingle | Nadine Szumilas Odilia B. J. Corneth Christian H. K. Lehmann Christian H. K. Lehmann Christian H. K. Lehmann Heike Schmitt Svenia Cunz Jolie G. Cullen Talyn Chu Anita Marosan Attila Mócsai Vladimir Benes Dietmar Zehn Diana Dudziak Diana Dudziak Diana Dudziak Rudi W. Hendriks Lars Nitschke Lars Nitschke Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections Frontiers in Immunology plasmacytoid dendritic cells Interferon-alpha Siglec TLR9 SLE |
| title | Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections |
| title_full | Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections |
| title_fullStr | Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections |
| title_full_unstemmed | Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections |
| title_short | Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections |
| title_sort | siglec h deficient mice show enhanced type i ifn responses but do not develop autoimmunity after influenza or lcmv infections |
| topic | plasmacytoid dendritic cells Interferon-alpha Siglec TLR9 SLE |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.698420/full |
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