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High-salt diet decreases mechanical thresholds in mice that is mediated by a CCR2-dependent mechanism
Anni Fan1, Oladayo Oladiran1, Xiang Qun Shi1
1The Alan Edwards Centre for Research on Pain, McGill University, 740, Dr. Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Background:
Though it is well-known that a high-salt diet (HSD) is associated with many chronic diseases, the effects of long-term high-salt intake on physiological functions and homeostasis remain elusive. In this study, we investigated whether and how an HSD affects mouse nociceptive thresholds, and myeloid cell trafficking and activation.
Methods:
Healthy C57BL/6 male and female mice were fed an HSD (containing 4% NaCl in chow and 1% NaCl in water) from the time of weaning for 3 to 4 months. Circulating monocytes, nerve macrophages, spinal microglia, and associated inflammatory responses were scrutinized using flow cytometry, immunohistochemistry, and quantitative real-time polymerase chain reaction (qPCR) approaches. Mouse pain sensitivity to mechanical stimuli was monitored with von Frey tests along the experimental duration.
Results:
Mice on an HSD have reduced mechanical thresholds. They feel more pain than those on a normal diet (ND), e.g., regular laboratory chow (0.3% NaCl in chow). An HSD induced not only a remarkable expansion of circulating monocytes, CCR2+Ly6Chi inflammatory monocytes in particular, but also an accumulation of CD11b+F4/80+ macrophages in the peripheral nerves and an activation of Iba-1+ spinal microglia. Replacing an HSD with a ND was unable to reverse the HSD-induced mechanical hypersensitivity or rescue the altered immune responses. However, treating HSD-fed mice with a chemokine receptor CCR2 antagonist effectively normalized the pain thresholds and immune cell profile in the periphery and spinal cord. An HSD failed to alter pain thresholds and myeloid cell activation in CCR2-deficient mice. Spinal microglial activation is required for HSD-induced mechanical hypersensitivity in male, but not in female mice.
Conclusion:
Overall, this study provides evidence that an HSD has a long-term impact on physiological function. CCR2-mediated cellular response, including myeloid cell trafficking and associated inflammation, plays pivotal roles in salt-dietary modulation of pain sensitivity.
Insights
A high-salt diet (HSD) reduces pain thresholds in mice by altering myeloid cell function via CCR2. This salt-induced hypersensitivity and immune cell changes persist even after diet reversal, highlighting long-term physiological impacts.
Area of Science:
- Neuroscience
- Immunology
- Physiology
Background:
- High-salt diet (HSD) is linked to chronic diseases, but its long-term effects on physiological functions remain unclear.
- This study investigates HSD's impact on mouse pain sensitivity and myeloid cell activity.
Purpose of the Study:
- To determine how long-term HSD affects nociceptive thresholds in mice.
- To investigate the role of myeloid cell trafficking and activation in HSD-induced physiological changes.
- To explore the involvement of the CCR2 pathway in salt-induced pain sensitivity.
Main Methods:
- Mice were fed an HSD (4% NaCl) or normal diet (ND) for 3-4 months.
- Flow cytometry, immunohistochemistry, and qPCR analyzed circulating monocytes, nerve macrophages, and spinal microglia.
- Pain sensitivity was assessed using von Frey tests; CCR2 antagonists and CCR2-deficient mice were used to probe pathway involvement.
Main Results:
- HSD significantly reduced mechanical pain thresholds, indicating increased pain sensitivity.
- HSD led to monocyte expansion, peripheral nerve macrophage accumulation, and spinal microglia activation.
- CCR2 antagonism or deficiency normalized pain sensitivity and immune cell profiles in HSD-fed mice; spinal microglia were essential for HSD-induced pain in males.
Conclusions:
- Long-term HSD has lasting detrimental effects on physiological functions, including pain sensitivity.
- CCR2-mediated myeloid cell trafficking and inflammation are critical in how salt intake modulates pain.
- Dietary salt's impact on pain is partly mediated by the CCR2 pathway, affecting immune cell responses.
