Acid-sensing ion channel 3 in macrophages, but not sensory neurons, mediates development of activity-induced muscle pain, 2025, Hayashi et al.

SNT Gatchaman

SNT Gatchaman

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Acid-sensing ion channel 3 in macrophages, but not sensory neurons, mediates development of activity-induced muscle pain
Hayashi; Lesnak; Plumb; Janowski; Rasmussen; Vignes; Flanagan; Berardi; Paradee; Sluka

Activity-induced pain is a significant symptom for people with chronic pain and reduces participation in daily activities and effective exercise programs. We previously showed that pharmacological blockade of ASIC3 locally in muscle, but not downregulation of ASIC3 in sensory neurons, prevents development of activity-induced muscle pain. Further, depleting macrophages from muscle prevents activity-induced pain. We therefore hypothesized that ASIC3 expression in muscle macrophages is necessary for development of activity-induced muscle pain by promoting release of pro-inflammatory cytokines.

We developed a conditional ASIC3 knockout mouse (ASIC3fl/fl) to test if removal of ASIC3 from macrophages prevents development of activity-induced pain. Cx3cr1Cre+/ASIC3fl/fl mice do not develop activity-induced pain; however, AdvCre+/ASIC3fl/fl had no effect on activity-induced pain. In contrast, carrageenan-induced muscle pain was prevented in both Cx3cr1Cre+/ASIC3fl/fl and AdvCre+/ASIC3fl/fl mice. Further, removal of ASIC3 from muscle macrophages, using a lentivirus expressing CRE injected into muscle from ASIC3fl/fl mice, attenuated activity-induced pain.

Flow cytometry revealed the proportion of muscle macrophages in muscle was decreased in Cx3cr1Cre+/ASIC3fl/fl compared to controls (Cx3cr1Cre-/ASIC3fl/fl), despite overall increases in myeloid cells and T-cells. Further in Cx3cr1Cre+/ASIC3fl/fl there was an attenuated release of the inflammatory cytokines GM-csf and TNFα from cultured macrophages treated with ATP and pH 6.5 when compared to controls.

Together these data show that ASIC3 in muscle macrophages plays a critical role in development of activity-induced muscle pain by modulating release of inflammatory cytokines.

HIGHLIGHTS
• Activity-induced pain is a significant barrier to participation in daily activities and effective exercise programs in individuals with chronic musculoskeletal pain. Fatigue metabolites released during exercise can activate their receptors to contribute to activity induced pain.

• Using a conditional knockout approach, we show removal of the acid-sensing ion channel 3 from muscle macrophages prevents activity-induced pain, proportion of macrophages in muscle, and reduces evoked release of inflammatory cytokines.

• Removal of ASIC3 from sensory neurons, using conditional knockouts, has no effect on development of activity-induced pain, but does prevent development of inflammatory pain.

• Activation of ASIC3 on muscle macrophages contributes to activity-induced pain by increasing release of inflammatory cytokines.

Web | Brain, Behavior, and Immunity | Paywall
 
That’s very interesting, and may provide a very specific answer for why malic acid nearly eliminates PEM for me, where the most immediate symptom is deep muscle pain.

I shared this paper a while ago:
Thread 'Malate initiates a proton-sensing pathway essential for pH regulation of inflammation, 2024, Chen et al.'
https://www.s4me.info/threads/malat...lation-of-inflammation-2024-chen-et-al.43873/

It shows that L-Malate inhibits IL-1B production in macrophages, which is the same cytokine implicated in this thread’s paper.
 
On other papers I’ve commented on the use of CX3CR1 Cre mouse models, because CX3CR1 is expressed in many different contexts and may confound results by knocking out the gene in an unintended cell type. There is a possibility that some of the behavioral assessments may have been impacted by knockout of these genes in microglia as well as muscle-resident macrophages. It seems unlikely as the signals they were studying were local and you probably wouldn’t expect the same ion sending to occur in the brain in response to a peripheral signal, but I suppose it’s a theoretical possibility. [Edit: the only reason I bring it up is because of previous findings of the same ion channel on peripheral and hypothalamic neurons both feeding into body temperature sensing https://sci-hub.st/10.1126/science.aaf7537]

However, the bulk of the important findings from this paper were directly looking at muscle tissue, so I would say the CX3CR1 model was an appropriate one.

[Edit: for anyone unfamiliar with the terminology, a Cre-lox mouse model is where you have a conditional deletion of a gene only in specific cell types that express another gene. So a CX3CR1cre+/ASIC3fl/fl model is one where the ASIC3 gene is knocked out only in cells expressing CX3CR1, which is primarily tissue resident macrophage and macrophage-like cells (but not exclusively). Fl/fl means “floxed” which is a reference to how the genes are snipped out of the genome]
 
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