Thymic macrophages consist of two populations with distinct localization and origin
- National Yang Ming Chiao Tung University, Taiwan
- Academia Sinica, Taiwan
- University of California, Berkeley, United States
Abstract
Tissue-resident macrophages are essential to protect from pathogen invasion and maintain organ homeostasis. The ability of thymic macrophages to engulf apoptotic thymocytes is well appreciated, but little is known about their ontogeny, maintenance, and diversity. Here, we characterized the surface phenotype and transcriptional profile of these cells and defined their expression signature. Thymic macrophages were most closely related to spleen red pulp macrophages and Kupffer cells and shared the expression of the transcription factor SpiC with these cells. Single-cell RNA sequencing showed that the macrophages in the adult thymus are composed of two populations distinguished by the expression of Timd4 and Cx3cr1. Remarkably, Timd4+ cells were located in the cortex, while Cx3cr1+ macrophages were restricted to the medulla and the cortico-medullary junction. Using shield chimeras, transplantation of embryonic thymuses, and genetic fate mapping, we found that the two populations have distinct origins. Timd4+ thymic macrophages are of embryonic origin, while Cx3cr1+ macrophages are derived from adult hematopoietic stem cells. Aging has a profound effect on the macrophages in the thymus. Timd4+ cells underwent gradual attrition, while Cx3cr1+ cells slowly accumulated with age and, in older mice, were the dominant macrophage population in the thymus. Altogether, our work defines the phenotype, origin, and diversity of thymic macrophages.
Data availability
The RNA Sequencing data of thymic macrophages and thymic dendritic cells are available at NCBI Gene Expression Omnibus (GEO) as part of GSE122108 and at www.immgen.org. The single cell RNA sequencing data is deposited at NCBI GEO under accession number GSE185460. The source data underlying Fig. 1G and H, Fig. 3B, D, and G, Fig. 5C, F, and I, Fig. 6B, E, G, and I, Fig. 7B, C, D, and G, Fig. 8B, D, E, and F, Fig. 1S4, Fig. 2S1, Fig. 2S2, Fig. 2S3, Fig. 5S1, and Fig. 5S2 are provided in the Source Data files. All other data supporting the findings of this study are available within the article.
-
Single-cell RNA-sequencing of thymic myeloid cells from Csf1rgfp/gfp (MaFIA) and Cd11cyfp/yfp miceNCBI Gene Expression Omnibus, GSE185460.
-
OpenSource Mononuclear Phagocytes ProjectNCBI Gene Expression Omnibus, GSE122108.
Article and author information
Author details
Funding
Ministry of Science and Technology, Taiwan (107-2320-B-010 -016 -MY3)
- Ivan L Dzhagalov
Ministry of Science and Technology, Taiwan (110-2320-B-A49A-521 -)
- Ivan L Dzhagalov
Ministry of Science and Technology, Taiwan (111-2320-B-A49 -031 -MY3)
- Ivan L Dzhagalov
Yen Tjing Ling Medical Foundation (CI-111-6)
- Ivan L Dzhagalov
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 experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee (IACUC) of National Yang Ming Chiao Tung University (animal protocols #1070506, and 1090301). All surgery was performed under Ketamine + Xylazine anesthesia, and every effort was made to minimize suffering.
Reviewing Editor
- Xiaoyu Hu, Tsinghua University, China
Publication history
- Received: October 31, 2021
- Preprint posted: November 4, 2021 (view preprint)
- Accepted: November 29, 2022
- Accepted Manuscript published: November 30, 2022 (version 1)
- Version of Record published: December 15, 2022 (version 2)
Copyright
© 2022, Zhou 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
-
- 787
- Page views
-
- 170
- Downloads
-
- 1
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
Thymic macrophages consist of two populations with distinct localization and origin
eLife 11:e75148.
https://doi.org/10.7554/eLife.75148
Further reading
-
- Developmental Biology
The acrosome is a membranous organelle positioned in the anterior portion of the sperm head and is essential for male fertility. Acrosome biogenesis requires the dynamic cytoskeletal shuttling of vesicles towards nascent acrosome which is regulated by a series of accessory proteins. However, much remains unknown about the molecular basis underlying this process. Here, we generated Ssh2 knock-out (KO) mice and HA-tagged Ssh2 knock-in (KI) mice to define the functions of Slingshot phosphatase 2 (SSH2) in spermatogenesis and demonstrated that as a regulator of actin remodeling, SSH2 is essential for acrosome biogenesis and male fertility. In Ssh2 KO males, spermatogenesis was arrested at the early spermatid stage with increased apoptotic index and the impaired acrosome biogenesis was characterized by defective transport/fusion of proacrosomal vesicles. Moreover, disorganized F-actin structures accompanied by excessive phosphorylation of COFILIN were observed in the testes of Ssh2 KO mice. Collectively, our data reveal a modulatory role for SSH2 in acrosome biogenesis through COFILIN-mediated actin remodeling and the indispensability of this phosphatase in male fertility in mice.
-
- Developmental Biology
- Evolutionary Biology
Wing dimorphism in insects is an evolutionarily adaptive trait to maximize insect fitness under various environments, by which the population could be balanced between dispersing and reproduction. Most studies concern the regulatory mechanisms underlying the stimulation of wing morph in aphids, but relatively little research addresses the molecular basis of wing loss. Here, we found that, while developing normally in winged-destined pea aphids, the wing disc in wingless-destined aphids degenerated 30-hr postbirth and that this degeneration was due to autophagy rather than apoptosis. Activation of autophagy in first instar nymphs reduced the proportion of winged aphids, and suppression of autophagy increased the proportion. REPTOR2, associated with TOR signaling pathway, was identified by RNA-seq as a differentially expressed gene between the two morphs with higher expression in the thorax of wingless-destined aphids. Further genetic analysis indicated that REPTOR2 could be a novel gene derived from a gene duplication event that occurred exclusively in pea aphids on autosome A1 but translocated to the sex chromosome. Knockdown of REPTOR2 reduced autophagy in the wing disc and increased the proportion of winged aphids. In agreement with REPTOR’s canonical negative regulatory role of TOR on autophagy, winged-destined aphids had higher TOR expression in the wing disc. Suppression of TOR activated autophagy of the wing disc and decreased the proportion of winged aphids, and vice versa. Co-suppression of TOR and REPTOR2 showed that dsREPTOR2 could mask the positive effect of dsTOR on autophagy, suggesting that REPTOR2 acted as a key regulator downstream of TOR in the signaling pathway. These results revealed that the TOR signaling pathway suppressed autophagic degradation of the wing disc in pea aphids by negatively regulating the expression of REPTOR2.
