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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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Autores principales: Szumilas, Nadine, Corneth, Odilia B. J., Lehmann, Christian H. K., Schmitt, Heike, Cunz, Svenia, Cullen, Jolie G., Chu, Talyn, Marosan, Anita, Mócsai, Attila, Benes, Vladimir, Zehn, Dietmar, Dudziak, Diana, Hendriks, Rudi W., Nitschke, Lars
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419311/
https://www.ncbi.nlm.nih.gov/pubmed/34497606
http://dx.doi.org/10.3389/fimmu.2021.698420
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author Szumilas, Nadine
Corneth, Odilia B. J.
Lehmann, Christian H. K.
Schmitt, Heike
Cunz, Svenia
Cullen, Jolie G.
Chu, Talyn
Marosan, Anita
Mócsai, Attila
Benes, Vladimir
Zehn, Dietmar
Dudziak, Diana
Hendriks, Rudi W.
Nitschke, Lars
author_facet Szumilas, Nadine
Corneth, Odilia B. J.
Lehmann, Christian H. K.
Schmitt, Heike
Cunz, Svenia
Cullen, Jolie G.
Chu, Talyn
Marosan, Anita
Mócsai, Attila
Benes, Vladimir
Zehn, Dietmar
Dudziak, Diana
Hendriks, Rudi W.
Nitschke, Lars
author_sort Szumilas, Nadine
collection PubMed
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.
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spelling pubmed-84193112021-09-07 Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections Szumilas, Nadine Corneth, Odilia B. J. Lehmann, Christian H. K. Schmitt, Heike Cunz, Svenia Cullen, Jolie G. Chu, Talyn Marosan, Anita Mócsai, Attila Benes, Vladimir Zehn, Dietmar Dudziak, Diana Hendriks, Rudi W. Nitschke, Lars Front Immunol Immunology 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. Frontiers Media S.A. 2021-08-23 /pmc/articles/PMC8419311/ /pubmed/34497606 http://dx.doi.org/10.3389/fimmu.2021.698420 Text en Copyright © 2021 Szumilas, Corneth, Lehmann, Schmitt, Cunz, Cullen, Chu, Marosan, Mócsai, Benes, Zehn, Dudziak, Hendriks and Nitschke https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Szumilas, Nadine
Corneth, Odilia B. J.
Lehmann, Christian H. K.
Schmitt, Heike
Cunz, Svenia
Cullen, Jolie G.
Chu, Talyn
Marosan, Anita
Mócsai, Attila
Benes, Vladimir
Zehn, Dietmar
Dudziak, Diana
Hendriks, Rudi W.
Nitschke, Lars
Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections
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 Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419311/
https://www.ncbi.nlm.nih.gov/pubmed/34497606
http://dx.doi.org/10.3389/fimmu.2021.698420
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