Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice
- University of California San Francisco, United States
- University of California, San Francisco, United States
- University California San Francisco, United States
Abstract
Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony stimulating factor 1 (CSF1) from injured sensory neurons as a mechanism contributing to nerve injury-induced pain. Here we show that intrathecal administration of CSF1, even in the absence of injury, is sufficient to induce pain behavior, but only in male mice. Transcriptional profiling and morphologic analyses after intrathecal CSF1 showed robust immune activation in male but not female microglia. CSF1 also induced marked expansion of lymphocytes within the spinal cord meninges, with preferential expansion of regulatory T-cells (Tregs) in female mice. Consistent with the hypothesis that Tregs actively suppress microglial activation in females, Treg deficient (Foxp3DTR) female mice showed increased CSF1-induced microglial activation and pain hypersensitivity equivalent to males. We conclude that sexual dimorphism in the contribution of microglia to pain results from Treg-mediated suppression of microglial activation and pain hypersensitivity in female mice.
Data availability
RNA sequencing data are available through GEO accession #GSE 184801All data generated or analysed during this study and required for conclusions to be drawn are included in the manuscript and supporting files.The upload can be identified at the following link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE184801
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Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female miceNCBI Gene Expression Omnibus, GSE184801.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (R35 NS097306)
- Allan Basbaum
Open Philathropy
- Allan Basbaum
Pew Charitable Trusts
- Anna Molofsky
National Institute of Mental Health (R01MH119349)
- Anna Molofsky
National Institute of Mental Health (DP2MH116507)
- Anna Molofsky
Burroughs Wellcome Fund
- Anna Molofsky
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: As noted in the description of the mice used in this study:"All mouse experiments were approved by UCSF Institutional Animal Care and Use Committee and conducted in accordance with the guidelines established by the Institutional Animal Care and Use Committee and Laboratory Animal Resource Center."Please note that this is a renewal that occurred during the course of the revision to the manuscript.APPROVAL NUMBER: AN183265-02DApproval Date: June 15, 2021Expiration Date: February 26, 2022
Copyright
© 2021, Kuhn 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.
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Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice
eLife 10:e69056.
https://doi.org/10.7554/eLife.69056
Further reading
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When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.
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When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
