Sex-distinct microglial activation and myeloid cell infiltration in the spinal cord after painful peripheral injury

Neurobiology of Pain, 2022 · DOI: https://doi.org/10.1016/j.ynpai.2022.100106 · Published: October 12, 2022

Neurology Pain Management Research Methodology & Design

Simple Explanation

Chronic pain is a widespread issue affecting millions, necessitating a deeper understanding of its molecular mechanisms to develop effective treatments. Microglial activation, implicated in chronic pain, has seen limited translational success due to compound specificity and incomplete understanding of microglial reactivity. This study uses a mouse model of complex regional pain syndrome (CRPS) to monitor microglial activation during pain progression, discovering that while both sexes exhibit spinal cord microglial activation, it is attenuated and delayed in females. The research identifies two distinct populations in the spinal cord: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells. Spinal cord TMEM119+ microglia are identified as the cellular source of cytokines IL6 and IL1β after peripheral injury.

Study Duration

7 weeks

Participants

Mice (C57BL/6J, Jax #00664, 9–11 weeks upon arrival, 11–12 weeks at study initiation; TMEM119-2A-EGFP (TMEM119-eGFP), Jax #031823, 9–11 weeks upon arrival, 11–12 weeks at study initiation)

Evidence Level

Not specified

Key Findings

1
Spinal cord microglial activation is attenuated and delayed in females compared to males after peripheral injury.
2
Two distinct populations of cells exist in the spinal cord after peripheral injury: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells.
3
TMEM119+ microglia are the primary cellular source of inflammatory cytokines IL6 and IL1β in the spinal cord after peripheral injury.

Research Summary

This study investigates sex-specific differences in spinal cord microglial activation and myeloid cell infiltration following peripheral injury using a mouse model of complex regional pain syndrome (CRPS). The researchers found that microglial activation is attenuated and delayed in females compared to males. They identified two distinct populations in the spinal cord parenchyma: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells. The study demonstrated that TMEM119+ microglia are the primary cellular source of inflammatory cytokines IL6 and IL1β in the spinal cord after peripheral injury, suggesting a potential therapeutic target for pain management.

Practical Implications

Analgesic Target Viability

Microglia remain a viable analgesic target for both males and females, provided the duration after injury is carefully considered.

Mechanism of Microglial Modulators

The analgesic properties of microglial modulators are likely related to their ability to suppress microglial-released cytokines.

Impact of Infiltrating Cells

Neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury, but their impact on pain persistence or resolution remains unclear.

Study Limitations

1
The study did not perform specific microglia-targeted interventions.
2
Morphological microglial activation is not necessarily equivalent to microglia-mediated neuroinflammation.
3
Further work is needed to understand the contributions of infiltrating cells into the spinal cord and their effects on the transition from acute to chronic pain.

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