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LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
BACKGROUND: Microglia plays crucial roles in Alzheimer’s disease (AD) development. Triggering receptor expressed on myeloid cells 2 (TREM2) in association with DAP12 mediates signaling affecting microglia function. Here we study the negative regulation of TREM2 functions by leukocyte immunoglobulin-...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206387/ https://www.ncbi.nlm.nih.gov/pubmed/35717259 http://dx.doi.org/10.1186/s13024-022-00550-y |
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author | Zhao, Peng Xu, Yuanzhong Jiang, Lu-Lin Fan, Xuejun Ku, Zhiqiang Li, Leike Liu, Xiaoye Deng, Mi Arase, Hisashi Zhu, Jay-Jiguang Huang, Timothy Y. Zhao, Yingjun Zhang, Chengcheng Xu, Huaxi Tong, Qingchun Zhang, Ningyan An, Zhiqiang |
author_facet | Zhao, Peng Xu, Yuanzhong Jiang, Lu-Lin Fan, Xuejun Ku, Zhiqiang Li, Leike Liu, Xiaoye Deng, Mi Arase, Hisashi Zhu, Jay-Jiguang Huang, Timothy Y. Zhao, Yingjun Zhang, Chengcheng Xu, Huaxi Tong, Qingchun Zhang, Ningyan An, Zhiqiang |
author_sort | Zhao, Peng |
collection | PubMed |
description | BACKGROUND: Microglia plays crucial roles in Alzheimer’s disease (AD) development. Triggering receptor expressed on myeloid cells 2 (TREM2) in association with DAP12 mediates signaling affecting microglia function. Here we study the negative regulation of TREM2 functions by leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), an inhibitory receptor bearing ITIM motifs. METHODS: To specifically interrogate LILRB2-ligand (oAβ and PS) interactions and microglia functions, we generated potent antagonistic LILRB2 antibodies with sub-nanomolar level activities. The biological effects of LILRB2 antagonist antibody (Ab29) were studied in human induced pluripotent stem cell (iPSC)–derived microglia (hMGLs) for migration, oAβ phagocytosis, and upregulation of inflammatory cytokines. Effects of the LILRB2 antagonist antibody on microglial responses to amyloid plaques were further studied in vivo using stereotaxic grafted microglia in 5XFAD mice. RESULTS: We confirmed the expression of both LILRB2 and TREM2 in human brain microglia using immunofluorescence. Upon co-ligation of the LILRB2 and TREM2 by shared ligands oAβ or PS, TREM2 signaling was significantly inhibited. We identified a monoclonal antibody (Ab29) that blocks LILRB2/ligand interactions and prevents TREM2 signaling inhibition mediated by LILRB2. Further, Ab29 enhanced microglia phagocytosis, TREM2 signaling, migration, and cytokine responses to the oAβ-lipoprotein complex in hMGL and microglia cell line HMC3. In vivo studies showed significantly enhanced clustering of microglia around plaques with a prominent increase in microglial amyloid plaque phagocytosis when 5XFAD mice were treated with Ab29. CONCLUSIONS: This study revealed for the first time the molecular mechanisms of LILRB2-mediated inhibition of TREM2 signaling in microglia and demonstrated a novel approach of enhancing TREM2-mediated microglia functions by blocking LILRB2-ligand interactions. Translationally, a LILRB2 antagonist antibody completely rescued the inhibition of TREM2 signaling by LILRB2, suggesting a novel therapeutic strategy for improving microglial functions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-022-00550-y. |
format | Online Article Text |
id | pubmed-9206387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-92063872022-06-19 LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions Zhao, Peng Xu, Yuanzhong Jiang, Lu-Lin Fan, Xuejun Ku, Zhiqiang Li, Leike Liu, Xiaoye Deng, Mi Arase, Hisashi Zhu, Jay-Jiguang Huang, Timothy Y. Zhao, Yingjun Zhang, Chengcheng Xu, Huaxi Tong, Qingchun Zhang, Ningyan An, Zhiqiang Mol Neurodegener Research Article BACKGROUND: Microglia plays crucial roles in Alzheimer’s disease (AD) development. Triggering receptor expressed on myeloid cells 2 (TREM2) in association with DAP12 mediates signaling affecting microglia function. Here we study the negative regulation of TREM2 functions by leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), an inhibitory receptor bearing ITIM motifs. METHODS: To specifically interrogate LILRB2-ligand (oAβ and PS) interactions and microglia functions, we generated potent antagonistic LILRB2 antibodies with sub-nanomolar level activities. The biological effects of LILRB2 antagonist antibody (Ab29) were studied in human induced pluripotent stem cell (iPSC)–derived microglia (hMGLs) for migration, oAβ phagocytosis, and upregulation of inflammatory cytokines. Effects of the LILRB2 antagonist antibody on microglial responses to amyloid plaques were further studied in vivo using stereotaxic grafted microglia in 5XFAD mice. RESULTS: We confirmed the expression of both LILRB2 and TREM2 in human brain microglia using immunofluorescence. Upon co-ligation of the LILRB2 and TREM2 by shared ligands oAβ or PS, TREM2 signaling was significantly inhibited. We identified a monoclonal antibody (Ab29) that blocks LILRB2/ligand interactions and prevents TREM2 signaling inhibition mediated by LILRB2. Further, Ab29 enhanced microglia phagocytosis, TREM2 signaling, migration, and cytokine responses to the oAβ-lipoprotein complex in hMGL and microglia cell line HMC3. In vivo studies showed significantly enhanced clustering of microglia around plaques with a prominent increase in microglial amyloid plaque phagocytosis when 5XFAD mice were treated with Ab29. CONCLUSIONS: This study revealed for the first time the molecular mechanisms of LILRB2-mediated inhibition of TREM2 signaling in microglia and demonstrated a novel approach of enhancing TREM2-mediated microglia functions by blocking LILRB2-ligand interactions. Translationally, a LILRB2 antagonist antibody completely rescued the inhibition of TREM2 signaling by LILRB2, suggesting a novel therapeutic strategy for improving microglial functions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-022-00550-y. BioMed Central 2022-06-18 /pmc/articles/PMC9206387/ /pubmed/35717259 http://dx.doi.org/10.1186/s13024-022-00550-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Zhao, Peng Xu, Yuanzhong Jiang, Lu-Lin Fan, Xuejun Ku, Zhiqiang Li, Leike Liu, Xiaoye Deng, Mi Arase, Hisashi Zhu, Jay-Jiguang Huang, Timothy Y. Zhao, Yingjun Zhang, Chengcheng Xu, Huaxi Tong, Qingchun Zhang, Ningyan An, Zhiqiang LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions |
title | LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions |
title_full | LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions |
title_fullStr | LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions |
title_full_unstemmed | LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions |
title_short | LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions |
title_sort | lilrb2-mediated trem2 signaling inhibition suppresses microglia functions |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206387/ https://www.ncbi.nlm.nih.gov/pubmed/35717259 http://dx.doi.org/10.1186/s13024-022-00550-y |
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