IL-5 mediates monocyte phenotype and pain outcomes in fibromyalgia
Ericka N Merriwether, Nilesh M Agalave, Dana L Dailey, Barbara A Rakel, Sandra J Kolker, Melissa E Lenert, William H Spagnola, Ying Lu, Katharine M Geasland, Lee-Ann H Allen, Michael D Burton, Kathleen A Sluka, Ericka N Merriwether, Nilesh M Agalave, Dana L Dailey, Barbara A Rakel, Sandra J Kolker, Melissa E Lenert, William H Spagnola, Ying Lu, Katharine M Geasland, Lee-Ann H Allen, Michael D Burton, Kathleen A Sluka
Abstract
Fibromyalgia (FM) is characterized by widespread chronic pain, fatigue, and somatic symptoms. The influence of phenotypic changes in monocytes on symptoms associated with FM is not fully understood. The primary aim of this study was to take a comprehensive whole-body to molecular approach in characterizing relationships between monocyte phenotype and FM symptoms in relevant clinical populations. Lipopolysaccharide-evoked and spontaneous secretion of IL-5 and other select cytokines from circulating monocytes was higher in women with FM compared to women without pain. In addition, greater secretion of IL-5 was significantly associated with pain and other clinically relevant psychological and somatic symptoms of FM. Furthermore, higher levels of pain and pain-related symptoms were associated with a lower percentage of intermediate monocytes (CD14++/CD16+) and a greater percentage of nonclassical monocytes (CD14+/CD16++) in women with FM. Based on findings from individuals with FM, we examined the role of IL-5, an atypical cytokine secreted from monocytes, in an animal model of widespread muscle pain. Results from the animal model show that IL-5 produces analgesia and polarizes monocytes toward an anti-inflammatory phenotype (CD206+). Taken together, our data suggest that monocyte phenotype and their cytokine profiles are associated with pain-related symptoms in individuals with FM. Furthermore, our data show that IL-5 has a potential role in analgesia in an animal model of FM. Thus, targeting anti-inflammatory cytokines such as IL-5 secreted by circulating leukocytes could serve as a promising intervention to control pain and other somatic symptoms associated with FM.
Trial registration: ClinicalTrials.gov NCT01888640.
Copyright © 2020 International Association for the Study of Pain.
Figures
![Figure 1.. LPS-stimulated human peripheral monocytes from…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7987864/bin/nihms-1631055-f0001.jpg)
Figure 2.. Difference in monocyte subpopulations in…
Figure 2.. Difference in monocyte subpopulations in between fibromyalgia (FM) and No Pain (NP) participants.
Figure 3.. Assessment of pain like behavior…
Figure 3.. Assessment of pain like behavior and IL-5 expression in established experimental model of…
Figure 4.. Effect of IL-5 on widespread…
Figure 4.. Effect of IL-5 on widespread muscle pain behavior and monocyte polarization.
A) Maximal…
- Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model of chronic muscle pain.Lenert ME, Szabo-Pardi TA, Burton MD. Lenert ME, et al. Mol Pain. 2023 Jan-Dec;19:17448069221110691. doi: 10.1177/17448069221110691. Mol Pain. 2023. PMID: 35712872 Free PMC article.
- Aquatic exercise improves the monocyte pro- and anti-inflammatory cytokine production balance in fibromyalgia patients.Ortega E, Bote ME, Giraldo E, García JJ. Ortega E, et al. Scand J Med Sci Sports. 2012 Feb;22(1):104-12. doi: 10.1111/j.1600-0838.2010.01132.x. Epub 2010 Jun 1. Scand J Med Sci Sports. 2012. PMID: 20536907
- Maximal Exercise Alters the Inflammatory Phenotype and Response of Mononuclear Cells.Slusher AL, Zúñiga TM, Acevedo EO. Slusher AL, et al. Med Sci Sports Exerc. 2018 Apr;50(4):675-683. doi: 10.1249/MSS.0000000000001480. Med Sci Sports Exerc. 2018. PMID: 29112629
- Stress, Inflammation and Pain: A Potential Role for Monocytes in Fibromyalgia-related Symptom Severity.Taylor AG, Fischer-White TG, Anderson JG, Adelstein KE, Murugesan M, Lewis JE, Scott MM, Gaykema RP, Goehler LE. Taylor AG, et al. Stress Health. 2016 Dec;32(5):503-513. doi: 10.1002/smi.2648. Epub 2015 Sep 29. Stress Health. 2016. PMID: 27925450
- Exercise in fibromyalgia and related inflammatory disorders: known effects and unknown chances.Ortega E, García JJ, Bote ME, Martín-Cordero L, Escalante Y, Saavedra JM, Northoff H, Giraldo E. Ortega E, et al. Exerc Immunol Rev. 2009;15:42-65. Exerc Immunol Rev. 2009. PMID: 19957871 Review.
- The peripheral Epac1/p-Cav-1 pathway underlies the disruption of the vascular endothelial barrier following skin/muscle incision and retraction-induced chronic postsurgical pain.Chen H, She Q, Liu Y, Chen J, Qin Y, Lu C. Chen H, et al. Ann Transl Med. 2022 Dec;10(24):1377. doi: 10.21037/atm-22-6069. Ann Transl Med. 2022. PMID: 36660643 Free PMC article.
- High-fat diet causes mechanical allodynia in the absence of injury or diabetic pathology.Tierney JA, Uong CD, Lenert ME, Williams M, Burton MD. Tierney JA, et al. Sci Rep. 2022 Sep 1;12(1):14840. doi: 10.1038/s41598-022-18281-x. Sci Rep. 2022. PMID: 36050326 Free PMC article.
- Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model of chronic muscle pain.Lenert ME, Szabo-Pardi TA, Burton MD. Lenert ME, et al. Mol Pain. 2023 Jan-Dec;19:17448069221110691. doi: 10.1177/17448069221110691. Mol Pain. 2023. PMID: 35712872 Free PMC article.
- Can neural markers be used for fibromyalgia clinical management?Castelo-Branco L, Cardenas-Rojas A, Pacheco-Barrios K, Teixeira PEP, Gonzalez-Mego P, Vasquez-Avila K, Cortez PC, Marduy A, Rebello-Sanchez I, Parente J, Marzouk S, Fregni F. Castelo-Branco L, et al. Princ Pract Clin Res. 2022 Jan-Mar;8(1):28-33. doi: 10.21801/ppcrj.2022.81.5. Epub 2022 Apr 24. Princ Pract Clin Res. 2022. PMID: 35677778 Free PMC article. No abstract available.
- Translating Outcomes from the Clinical Setting to Preclinical Models: Chronic Pain and Functionality in Chronic Musculoskeletal Pain.Lenert ME, Gomez R, Lane BT, Dailey DL, Vance CGT, Rakel BA, Crofford LJ, Sluka KA, Merriwether EN, Burton MD. Lenert ME, et al. Pain Med. 2022 Sep 30;23(10):1690-1707. doi: 10.1093/pm/pnac047. Pain Med. 2022. PMID: 35325207 Free PMC article.
- Research Support, N.I.H., Extramural
- Animals
- Female
- Fibromyalgia* / complications
- Humans
- Interleukin-5
- Monocytes*
- Pain / etiology
- Phenotype
- IL5 protein, human
- Interleukin-5
- ClinicalTrials.gov/NCT01888640
- Full Text Sources
- Medical
- Research Materials
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![Figure 2.. Difference in monocyte subpopulations in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7987864/bin/nihms-1631055-f0002.jpg)
![Figure 3.. Assessment of pain like behavior…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7987864/bin/nihms-1631055-f0003.jpg)
Figure 4.. Effect of IL-5 on widespread…
Figure 4.. Effect of IL-5 on widespread muscle pain behavior and monocyte polarization.
A) Maximal…
- Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model of chronic muscle pain.Lenert ME, Szabo-Pardi TA, Burton MD. Lenert ME, et al. Mol Pain. 2023 Jan-Dec;19:17448069221110691. doi: 10.1177/17448069221110691. Mol Pain. 2023. PMID: 35712872 Free PMC article.
- Aquatic exercise improves the monocyte pro- and anti-inflammatory cytokine production balance in fibromyalgia patients.Ortega E, Bote ME, Giraldo E, García JJ. Ortega E, et al. Scand J Med Sci Sports. 2012 Feb;22(1):104-12. doi: 10.1111/j.1600-0838.2010.01132.x. Epub 2010 Jun 1. Scand J Med Sci Sports. 2012. PMID: 20536907
- Maximal Exercise Alters the Inflammatory Phenotype and Response of Mononuclear Cells.Slusher AL, Zúñiga TM, Acevedo EO. Slusher AL, et al. Med Sci Sports Exerc. 2018 Apr;50(4):675-683. doi: 10.1249/MSS.0000000000001480. Med Sci Sports Exerc. 2018. PMID: 29112629
- Stress, Inflammation and Pain: A Potential Role for Monocytes in Fibromyalgia-related Symptom Severity.Taylor AG, Fischer-White TG, Anderson JG, Adelstein KE, Murugesan M, Lewis JE, Scott MM, Gaykema RP, Goehler LE. Taylor AG, et al. Stress Health. 2016 Dec;32(5):503-513. doi: 10.1002/smi.2648. Epub 2015 Sep 29. Stress Health. 2016. PMID: 27925450
- Exercise in fibromyalgia and related inflammatory disorders: known effects and unknown chances.Ortega E, García JJ, Bote ME, Martín-Cordero L, Escalante Y, Saavedra JM, Northoff H, Giraldo E. Ortega E, et al. Exerc Immunol Rev. 2009;15:42-65. Exerc Immunol Rev. 2009. PMID: 19957871 Review.
- The peripheral Epac1/p-Cav-1 pathway underlies the disruption of the vascular endothelial barrier following skin/muscle incision and retraction-induced chronic postsurgical pain.Chen H, She Q, Liu Y, Chen J, Qin Y, Lu C. Chen H, et al. Ann Transl Med. 2022 Dec;10(24):1377. doi: 10.21037/atm-22-6069. Ann Transl Med. 2022. PMID: 36660643 Free PMC article.
- High-fat diet causes mechanical allodynia in the absence of injury or diabetic pathology.Tierney JA, Uong CD, Lenert ME, Williams M, Burton MD. Tierney JA, et al. Sci Rep. 2022 Sep 1;12(1):14840. doi: 10.1038/s41598-022-18281-x. Sci Rep. 2022. PMID: 36050326 Free PMC article.
- Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model of chronic muscle pain.Lenert ME, Szabo-Pardi TA, Burton MD. Lenert ME, et al. Mol Pain. 2023 Jan-Dec;19:17448069221110691. doi: 10.1177/17448069221110691. Mol Pain. 2023. PMID: 35712872 Free PMC article.
- Can neural markers be used for fibromyalgia clinical management?Castelo-Branco L, Cardenas-Rojas A, Pacheco-Barrios K, Teixeira PEP, Gonzalez-Mego P, Vasquez-Avila K, Cortez PC, Marduy A, Rebello-Sanchez I, Parente J, Marzouk S, Fregni F. Castelo-Branco L, et al. Princ Pract Clin Res. 2022 Jan-Mar;8(1):28-33. doi: 10.21801/ppcrj.2022.81.5. Epub 2022 Apr 24. Princ Pract Clin Res. 2022. PMID: 35677778 Free PMC article. No abstract available.
- Translating Outcomes from the Clinical Setting to Preclinical Models: Chronic Pain and Functionality in Chronic Musculoskeletal Pain.Lenert ME, Gomez R, Lane BT, Dailey DL, Vance CGT, Rakel BA, Crofford LJ, Sluka KA, Merriwether EN, Burton MD. Lenert ME, et al. Pain Med. 2022 Sep 30;23(10):1690-1707. doi: 10.1093/pm/pnac047. Pain Med. 2022. PMID: 35325207 Free PMC article.
- Research Support, N.I.H., Extramural
- Animals
- Female
- Fibromyalgia* / complications
- Humans
- Interleukin-5
- Monocytes*
- Pain / etiology
- Phenotype
- IL5 protein, human
- Interleukin-5
- ClinicalTrials.gov/NCT01888640
- Full Text Sources
- Medical
- Research Materials
![Figure 4.. Effect of IL-5 on widespread…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7987864/bin/nihms-1631055-f0004.jpg)
Source: PubMed