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OnabotulinumtoxinA alters pro- and anti-inflammatory dural macrophage response to CSD in female mice
Aaron J Schain1,2, Diego Delgado Fajardo1, Andrew M Strassman1,2
1Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Abstract:
AimCortical spreading depression (CSD), the neural correlate of migraine aura, has been shown to cause activation of dural nociceptive neurons as well as immune cells, among which macrophages (MPs) are the most abundant and reactive. OnabotulinumtoxinA (onbotA) is used to treat chronic migraine but the mechanism of action is not fully understood. Here we investigate the role of meningeal MPs in a model of migraine activation and evaluate whether onabotA has an effect on their response.MethodsWe use our previously developed method to determine meningeal MP activation based on shape changes using time-lapse in vivo multiphoton microscopy.ResultsWe found that a small subset (∼10%) of MPs contracted their processes in response to CSD induction, but only in female mice. A similar subset of MPs contracted with lipopolysaccharide injection, suggesting that this is an M1-like response. Together this may provide insight into the phenotypic differences of migraine across males and females. We also found a small subset of MPs (∼10%) that expanded their processes in response to IL-10 (presumably an M2-like response), but were not affected by CSD. In female mice, pre-treatment with onabotA (i) reduces overall MP number in the dura, (ii) reduces pro-inflammatory M1 MP response and (iii) increases anti-inflammatory M2 response post-CSD compared to pretreatment with saline.ConclusionThis suggests that the mechanism of action of onabotA may not be simply due to its effects on nociceptors, but also due to an additional anti-inflammatory effect on the environment of the dura.
Insights
Cortical spreading depression (CSD) activates meningeal macrophages. OnabotulinumtoxinA (onbotA) treatment in female mice reduced pro-inflammatory macrophages and increased anti-inflammatory ones, suggesting a novel therapeutic mechanism for migraine.
Area of Science:
- Neuroscience
- Immunology
- Migraine Pathophysiology
Background:
- Cortical spreading depression (CSD) is linked to migraine aura and activates dural nociceptive neurons and immune cells, particularly macrophages (MPs).
- The mechanism of action for OnabotulinumtoxinA (onbotA), a chronic migraine treatment, remains incompletely understood.
- Meningeal macrophages play a crucial role in the neuroinflammatory response during migraine.
Purpose of the Study:
- To investigate the role of meningeal macrophages in a migraine model.
- To determine the effect of OnabotulinumtoxinA (onbotA) on macrophage activation during CSD.
- To explore potential sex-based differences in migraine pathophysiology and treatment response.
Main Methods:
- Time-lapse in vivo multiphoton microscopy was used to assess meningeal macrophage activation based on shape changes.
- CSD was induced to model migraine activation.
- Macrophage responses were analyzed in female mice pre-treated with onbotA or saline.
Main Results:
- CSD induction caused a subset of macrophages (∼10%) to contract processes, specifically in female mice, indicative of an M1-like response.
- Lipopolysaccharide injection elicited a similar macrophage response, supporting the M1-like classification.
- Interleukin-10 (IL-10) induced a subset of macrophages (∼10%) to expand processes (M2-like response), unaffected by CSD.
- OnabotA pre-treatment in female mice significantly reduced overall macrophage numbers, decreased M1 pro-inflammatory responses, and increased M2 anti-inflammatory responses post-CSD compared to saline controls.
Conclusions:
- OnabotA's therapeutic effect in chronic migraine may involve anti-inflammatory actions on the dural environment, beyond its effects on nociceptors.
- Meningeal macrophages exhibit distinct responses to CSD and inflammatory stimuli, with potential sex-specific differences.
- The findings suggest a novel mechanism for onbotA involving modulation of macrophage polarization in the dura mater.
