Neuron-associated macrophage proliferation in the sensory ganglia is associated with peripheral nerve injury-induced neuropathic pain involving CX3CR1 signaling

Abstract

Resident macrophages are distributed across all tissues and are highly heterogeneous due to adaptation to different tissue-specific environments. The resident macrophages of the sensory ganglia (sensory neuron-associated macrophages, sNAMs) are in close contact with the cell body of primary sensory neurons and might play physiological and pathophysiological roles. After peripheral nerve injury, there is an increase in the population of macrophage in the sensory ganglia, which have been implicated in different conditions, including neuropathic pain development. However, it is still under debate whether macrophage accumulation in the sensory ganglia after peripheral nerve injury is due to the local proliferation of resident macrophages or a result of blood monocyte infiltration. Here, we confirmed that the number of macrophages increased in the sensory ganglia after the spared nerve injury (SNI) model in mice. Using different approaches, we found that the increase in the number of macrophages in the sensory ganglia after SNI is a consequence of the proliferation of resident CX3CR1+ macrophages, which participate in the development of neuropathic pain, but not due to infiltration of peripheral blood monocytes. These proliferating macrophages are the source of pro-inflammatory cytokines such as TNF and IL-1b. In addition, we found that CX3CR1 signaling is involved in the sNAMs proliferation and neuropathic pain development after peripheral nerve injury. In summary, these results indicated that peripheral nerve injury leads to sNAMs proliferation in the sensory ganglia in a CX3CR1-dependent manner accounting for neuropathic pain development. In conclusion, sNAMs proliferation could be modulated to change pathophysiological conditions such as chronic neuropathic pain.

Data availability

All data generated or analyzed during this study are included in the manuscript. Public scRNA-seq data are available in Gene Expression Omnibus (GEO) database under the series number GSE139103 (Avraham et al. 2020).

The following previously published data sets were used

Article and author information

Author details

  1. Rafaela Mano Guimarães

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  2. Conceição Elidianne Aníbal-Silva

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  3. Marcela Davoli-Ferreira

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  4. Francisco Isaac Fernandes Gomes

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  5. Atlante Silva Mendes

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  6. Maria Claudia Magalhães Cavallini

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  7. Miriam Mendes Fonseca

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  8. Samara Damasceno

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  9. Larissa Pinto Andrade

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  10. Marco Colonna

    Department of Pathology and Immunology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Cyril Rivat

    Institut des Neurosciences de Montpellier, Université de Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Fernando Q Cunha

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  13. José C Alves-Filho

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  14. Thiago Mattar Cunha

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    For correspondence
    thicunha@fmrp.usp.br
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1084-0065

Funding

The authors declare that there was no funding for this work.

Reviewing Editor

  1. Florent Ginhoux, Agency for Science Technology and Research, Singapore

Ethics

Animal experimentation: Animal care and handling procedures were under the guidelines of the International Association for the Study of Pain for those animals used in pain research and were approved by the Committee for Ethics in Animal Research of the Ribeirao Preto Medical School- University of São Paulo (Process number 002/2017).

Version history

  1. Received: March 9, 2022
  2. Preprint posted: March 24, 2022 (view preprint)
  3. Accepted: May 22, 2023
  4. Accepted Manuscript published: May 31, 2023 (version 1)
  5. Version of Record published: June 14, 2023 (version 2)

Copyright

© 2023, Guimarães 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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  1. Rafaela Mano Guimarães
  2. Conceição Elidianne Aníbal-Silva
  3. Marcela Davoli-Ferreira
  4. Francisco Isaac Fernandes Gomes
  5. Atlante Silva Mendes
  6. Maria Claudia Magalhães Cavallini
  7. Miriam Mendes Fonseca
  8. Samara Damasceno
  9. Larissa Pinto Andrade
  10. Marco Colonna
  11. Cyril Rivat
  12. Fernando Q Cunha
  13. José C Alves-Filho
  14. Thiago Mattar Cunha
(2023)
Neuron-associated macrophage proliferation in the sensory ganglia is associated with peripheral nerve injury-induced neuropathic pain involving CX3CR1 signaling
eLife 12:e78515.
https://doi.org/10.7554/eLife.78515

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https://doi.org/10.7554/eLife.78515

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