Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice
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
-
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.
Metrics
-
- 3,640
- views
-
- 723
- downloads
-
- 57
- 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
-
- Cancer Biology
- Neuroscience
Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a mouse model for head and neck cancer and neuronal tracing, we show that tumor-infiltrating nerves connect to distinct brain areas. The activation of this neuronal circuitry altered behaviors (decreased nest-building, increased latency to eat a cookie, and reduced wheel running). Tumor-infiltrating nociceptor neurons exhibited heightened calcium activity and brain regions receiving these neural projections showed elevated Fos as well as increased calcium responses compared to non-tumor-bearing counterparts. The genetic elimination of nociceptor neurons decreased brain Fos expression and mitigated the behavioral alterations induced by the presence of the tumor. While analgesic treatment restored nesting and cookie test behaviors, it did not fully restore voluntary wheel running indicating that pain is not the exclusive driver of such behavioral shifts. Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer.
-
- Neuroscience
Emotional responsiveness in neonates, particularly their ability to discern vocal emotions, plays an evolutionarily adaptive role in human communication and adaptive behaviors. The developmental trajectory of emotional sensitivity in neonates is crucial for understanding the foundations of early social-emotional functioning. However, the precise onset of this sensitivity and its relationship with gestational age (GA) remain subjects of investigation. In a study involving 120 healthy neonates categorized into six groups based on their GA (ranging from 35 and 40 weeks), we explored their emotional responses to vocal stimuli. These stimuli encompassed disyllables with happy and neutral prosodies, alongside acoustically matched nonvocal control sounds. The assessments occurred during natural sleep states using the odd-ball paradigm and event-related potentials. The results reveal a distinct developmental change at 37 weeks GA, marking the point at which neonates exhibit heightened perceptual acuity for emotional vocal expressions. This newfound ability is substantiated by the presence of the mismatch response, akin to an initial form of adult mismatch negativity, elicited in response to positive emotional vocal prosody. Notably, this perceptual shift’s specificity becomes evident when no such discrimination is observed in acoustically matched control sounds. Neonates born before 37 weeks GA do not display this level of discrimination ability. This developmental change has important implications for our understanding of early social-emotional development, highlighting the role of gestational age in shaping early perceptual abilities. Moreover, while these findings introduce the potential for a valuable screening tool for conditions like autism, characterized by atypical social-emotional functions, it is important to note that the current data are not yet robust enough to fully support this application. This study makes a substantial contribution to the broader field of developmental neuroscience and holds promise for future research on early intervention in neurodevelopmental disorders.