MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis
Abstract
Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury and disease.
Data availability
Sequencing data has been deposited in GEO under the accession code GSE213739Code used to analyze sequencing data was uploaded at Source Code File 1All data generated or analyzed during this study are included in manuscript source data files
Article and author information
Author details
Funding
National Institutes of Health (NIA AG072305)
- Dwight E Bergles
National Multiple Sclerosis Society (FAN-1707-28857)
- Em P Harrington
Dr. Miriam and Sheldon G Adelson Medical Research Foundation
- Dwight E Bergles
National Science Foundation
- Riley B Catenacci
National Institutes of Health (R01 NS041435)
- Peter A Calabresi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures were performed according to protocols approved by the Johns Hopkins Animal Care and Use Committee protocol #MO22M158.
Copyright
© 2023, Harrington et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,921
- views
-
- 446
- downloads
-
- 16
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
Systemic blood coagulation accompanies inflammation during severe infections like sepsis and COVID. We previously established a link between coagulopathy and pyroptosis, a vital defense mechanism against infection. During pyroptosis, the formation of gasdermin-D (GSDMD) pores on the plasma membrane leads to the release of tissue factor (TF)-positive microvesicles (MVs) that are procoagulant. Mice lacking GSDMD release fewer of these procoagulant MVs. However, the specific mechanisms coupling the activation of GSDMD to MV release remain unclear. Plasma membrane rupture (PMR) in pyroptosis was recently reported to be actively mediated by the transmembrane protein Ninjurin-1 (NINJ1). Here, we show that NINJ1 promotes procoagulant MV release during pyroptosis. Haploinsufficiency or glycine inhibition of NINJ1 limited the release of procoagulant MVs and inflammatory cytokines, and partially protected against blood coagulation and lethality triggered by bacterial flagellin. Our findings suggest a crucial role for NINJ1-dependent PMR in inflammasome-induced blood coagulation and inflammation.
-
- Immunology and Inflammation
Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on an H-2Dd background restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo.