Science Immunology
February 20, 2026; Vol. 11; epub
[published by the American Association for the Advancement of Science]
Jaewon Sim, Elizabeth O’Guin, Chiho Sugimoto, Sophie Laumet, and 15 more; From Michigan State University, the University of North Carolina at Chapel Hill, the University of Kansas Medical Center, and the University Hospital Regensburg, Germany. This study cites 100 references.
The assessment in this study used both mouse and human subjects. The human arm of this study used 245 subjects. The objective of this study was to investigate whether IL-10 mediates the relationship between monocytes and chronic posttraumatic pain.
This study used preclinical and human approaches to define the role of IL-10–producing monocytes in pain resolution and to determine whether this mechanism contributes to sex differences.
The human subjects suffered from whiplash injuries. Their musculoskeletal pain severity was assessed in the immediate aftermath of traumatic collision exposure and at 8 weeks and 3 months by asking participants to rate their pain severity in the past week via a 0 to 10 numeric rating scale.
BACKGROUND FROM DAN MURPHY:
Classically, the monocyte is located in the blood where it travels to tissues where it differentiates into the macrophage, the primary cell of innate immune response.
Cytokines are proteins that are made by immune system cells.
Pro-inflammatory cytokines (TNF-alpha, IL-1beta; IL-6, IL-8) increase pain.
Anti-inflammatory cytokines reduce pain. The primary anti-inflammatory cytokine is interleukin-10 (IL-10). IL-10’s antinociceptive role in animals and humans is well established.
The production of IL-10 is dependent upon a molecule called resolvins series D.
Resolvins series D are made from the essential omega-3 fatty acid docosahexaenoic acid (DHA): See these Article Reviews:
28-20: Inflammation Resolution: A Dual-Pronged Approach to Averting Cytokine Storms in COVID-19
7-23: Acute Inflammatory Response Via Neutrophil Activation Protects Against the Development of Chronic Pain
23-24: Role of Resolvins in Inflammatory and Neuropathic Pain
Importantly, the ability to make resolvins is impaired by both steroidal and nonsteroidal anti-inflammatory drugs:
7-23: Acute Inflammatory Response Via Neutrophil Activation Protects Against the Development of Chronic Pain
KEY POINTS FROM THIS ARTICLE:
1) “Chronic pain is a prevalent health issue affecting more than 100 million individuals in the United States and incurring major health care costs.”
2) “Women frequently experience longer-lasting pain than men, indicating delayed pain resolution.”
- “There is a distinct female predominance in most chronic pain syndromes, likely driven by slower pain resolution in women.”
- “The slower resolution of pain in women increases their risk of transitioning to chronic pain.”
3) “Given the strong association between the immune system and pain, as well as sex differences in immune responses, immune mechanisms may contribute to sex differences in pain.”
4) Findings:
- Nociceptive neurons detect noxious, potentially tissue-damaging stimuli and relay pain signals to the central nervous system.
- These neurons have cytokine receptors, enabling direct communication between immune cells and these neurons. [Important]
- Anti-inflammatory cytokine interleukin-10 (IL-10) from monocytes resolve inflammatory pain by signaling to sensory neurons.
- Male animals exhibited faster pain resolution than females, which was associated with higher numbers of IL-10 and monocytes.
- “Expression of proinflammatory cytokines IL-6, IL-1β, and TNF-alpha was reduced by IL-10.”
- Proinflammatory cytokine levels are inversely correlated with IL-10 levels.
- “In humans, pain resolved faster in men than in women after traumatic injury [whiplash] and was associated with higher circulating monocytes and IL-10 levels in men.”
5) “Proinflammatory cytokines such as tumor necrosis factor–α (TNFα), interleukin-1β (IL-1β), and IL-6 increase the excitability of nociceptors, thereby inducing nociception.”
6) “IL-10 is an important antinociceptive cytokine, with its effect traditionally linked to suppression of inflammation.”
- However, the expression of the IL-10 receptor (IL-10R) on nociceptive neurons raises the possibility of direct action of IL-10 on neurons.
7) Increasing androgen [testosterone] signaling enables males to have more IL-10 and monocytes than females.
- In humans, men resolved persistent traumatic pain faster than women.
8) IL-10 exerts antinociceptive effects.
- IL-10 promotes the resolution of inflammatory pain and the higher IL-10 levels in males contribute to their faster pain resolution.
9) Monocytes, rather than macrophages, are the principal source of IL-10, and monocytes are more abundant in males than in females.
- IL-10 and monocytes are critical for inflammatory pain resolution.
- “Monocyte deficiency impedes pain resolution, likely by lowering IL-10 production.”
10) Resolvins Series D [the omega-3 connection]:
- Resolvin series D is a pro-resolving lipid mediator that resolves inflammatory pain.
- Resolvin series D expedites pain resolution by up-regulating IL-10 from monocytes. [Very Important]
- “[Resolvin series D] increased monocyte and macrophage numbers.”
- “[Resolvin series D] accelerate pain resolution via IL-10 and monocytes in both sexes.” [Important]
- Enhancing IL-10 and monocytes with [resolvin series D] accelerated pain resolution in both sexes.
- Increasing IL-10 and monocytes with [resolvin series D] alleviated pain in both sexes, highlighting the therapeutic potential of enhancing IL-10 and monocytes for treating sex-biased pain conditions. [Important]
11) IL-10 expression is higher in males than in females.
- “Men resolve pain faster than women, which is associated with higher levels of monocytes and IL-10.”
12) Human Study:
- The authors analyzed human data from the immediate aftermath of traumatic injury, primarily after motor vehicle accidents.
- “Acute pain severity on day 0 was comparably high in both sexes, with no significant difference observed.”
- “Over the course of 84 days, pain decreased in men faster than in women, highlighting sex differences in pain resolution.”
- “Men also exhibited higher plasma IL-10 levels than women after trauma.”
- “Circulating IL-10 levels were negatively correlated with pain severity at 84 days, indicating that higher IL-10 levels were associated with faster pain resolution.”
- “[Men also] had a higher percentage of circulating monocytes.”
- The number of monocytes exhibited a negative correlation with pain severity at 84 days.
- “Monocyte and IL-10 levels were strongly correlated.”
- “IL-10 mediates the relationship between monocytes and pain resolution.”
- “Men have higher levels of IL-10 and monocytes, both of which are associated with faster pain resolution.” [Very Important]
13) Androgens [testosterone]:
- “Androgen-mediated pain relief has been reported in inflammatory and musculoskeletal pain in rodents and humans.”
- “The antinociceptive role of androgens [testosterone] has been reported in preclinical models and human studies of inflammatory pain and musculoskeletal pain.”
- The greater abundance of IL-10 and monocytes in males is driven by androgen [testosterone] signaling.
- Cutaneous topical application of testosterone can alleviate musculoskeletal pain.
- “Androgen signaling promoted IL-10 production by monocytes, driving sex differences in IL-10 and monocyte abundance.”
- In humans experiencing traumatic injury, males resolve pain faster than females, which is driven by androgen [testosterone] signaling that enhances IL-10 levels in males.
- “Androgen signaling in monocytes facilitates IL-10 production to drive pain resolution.” [Important]
- “Loss of androgen signaling in males reduces IL-10 monocytes and delays pain resolution.”
- “Androgen signaling in monocytes enhances IL-10 production, thereby facilitating pain resolution.”
- “We found that IL-10 production is driven by androgen [testosterone] signaling in monocytes.”
14) Conclusions:
- Monocytes and IL-10 levels are associated with sex-biased pain resolution of traumatic injury in human patients. [Important]
- “These results highlight an important role for cross-talk between IL-10 and immune cells in resolving inflammatory pain.”
- IL-10 and monocytes are required to resolve inflammatory pain.
- “IL-10 exerts anti-inflammatory effects by suppressing the transcription of proinflammatory cytokines.” [Key Point]
- “Emerging evidence reveals an underappreciated role for immune cells in pain resolution.”
- “Sex differences in pain resolution are driven by differing levels of IL-10.”
- Monocyte-derived IL-10 is a critical mediator of communication between infiltrating immune cells and sensory neurons during pain resolution.
- “Our work demonstrates a role for these monocytes’ regulation of pain duration and sex differences.”
15) Editor’s Summary:
- “Women experience slower pain resolution and are more susceptible to developing chronic pain.”
- “IL-10–producing monocytes signal to sensory neurons to drive faster pain resolution in males.”
- Androgen [testosterone] signaling promotes accumulation of IL-10 and monocytes for pain resolution, and the effects are elicited by the [omega-3] lipid mediator resolvin series D.
- “In humans experiencing traumatic injury, pain resolved faster in men than women and was associated with higher IL-10 levels.”
- “These findings identify a role for monocytes in contributing to sex differences in pain resolution.”
COMMENTS FROM DAN MURPHY:
Inflammation alters the threshold of the pain afferent. See Article Review 29-09: The Origin of all Pain is Inflammation and the Inflammatory Response
Inflammatory proteins called cytokines increase pain. The primary inflammatory cytokines are TNF-alpha, IL-1beta; IL-6, IL-8. See books Younger Next Year and The Great Nerve, (below).
From the same references, the primary anti-inflammatory cytokine is interleukin-10 (IL-10).
Most Importantly, the following study (not yet reviewed) indicates meaningful increases of IL-10 following joint adjusting:
Attenuation Effect of Spinal Manipulation on Neuropathic Pain and Postoperative Pain Through Activating Endogenous Anti-inflammatory Cytokine Interleukin-10; Journal of Manipulative and Physiological Therapeutics; January 2016; Vol. 39; No. 1; pp. 42-53.
Perhaps that is one of the explanations for why joint adjusting helps people with pain. And we should all be taking our omega-3s to optimize resolvins.
