Regular swimming exercise prevented the acute and persistent mechanical muscle hyperalgesia by modulation of macrophages phenotypes and inflammatory cytokines via PPARγ receptors

Azambuja, Graciana de; Jorge, Carolina Ocanha; Gomes, Bpfa; Lourenço, Hayla R.; Simabuco, Fernando Moreira; Oliveira-Fusaro, Maria Claudia G.

doi:10.1016/j.bbi.2021.05.002

Cited by 11 publications

(19 citation statements)

References 68 publications

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“…Macrophages are plastic and change their phenotype in response to the external environment; the current study shows an increase in proportion of M1 macrophages in the muscle after induction of muscle pain in sedentary mice. This is in agreement with prior work showing an increase in M1 macrophages in the muscles of sedentary mice following injection of carrageenan ( 13 ). M1 macrophages release pro-inflammatory cytokines while M2 release antiinflammatory cytokines.…”

Section: Discussionsupporting

confidence: 93%

“…The current study also showed prior physical activity results in a higher proportion of macrophages demonstrating the M2 and M0 phenotype, and a lower proportion of the M1 phenotype, in the gastrocnemius muscle after induction of the pain model in both males and females. This agrees with prior work which showed increases in the M2 macrophage phenotype in muscle from uninjured animals and increases in M2 and decreases in M1 phenotypes in the muscle or at the site of nerve injury after exercise ( 13, 15, 17, 79 ). The higher proportion of antiinflammatory M2 macrophages could account for the attenuated immune response observed with RNA sequencing since M2 macrophages secrete anti-inflammatory cytokines such as IL-10 which protects against development of pain in several animal models ( 13, 15, 17, 80–83 ).…”

Section: Discussionsupporting

confidence: 93%

“…Macrophages play a critical role in development of muscle hyperalgesia as depletion of muscle macrophages and elimination of P2X4 receptors on muscle macrophages prevents hyperalgesia (11)(12)(13)(14). Macrophages are plastic and change their phenotype in response to the external environment; the current study shows an increase in proportion of M1 macrophages in the muscle after induction of muscle pain in sedentary mice.…”

Section: Muscle Pain and Immune Cellsmentioning

confidence: 51%

“…The copyright holder for this preprint this version posted December 10, 2022. ; https://doi.org/10.1101/2022.12.07.519473 doi: bioRxiv preprint in muscle from uninjured animals and increases in M2 and decreases in M1 phenotypes in the muscle or at the site of nerve injury after exercise (13,15,17,79). The higher proportion of antiinflammatory M2 macrophages could account for the attenuated immune response observed with RNA sequencing since M2 macrophages secrete anti-inflammatory cytokines such as IL-10 which protects against development of pain in several animal models (13,15,17,(80)(81)(82)(83). For example, increasing expression of IL-10 in the knee of canines with osteoarthritis reduces veterinary and owner pain assessments (80).…”

Section: Impact Of Prior Physical Activity On Immune Mechanismsmentioning

confidence: 99%

“…Similarly, in models of neuropathic pain, macrophages at the site of injury play a key role in the production of hyperalgesia (15,16), suggesting local immune mechanisms are important for pain development. Further, regular physical activity alters macrophage phenotype in skeletal muscle by increasing the number of anti-inflammatory macrophages (M2), and blockade of antiinflammatory cytokine receptors (IL-4, IL-10) at the site of insult prevents the analgesia produced by regular physical activity (13,(17)(18)(19)(20); however, these studies were only done in male mice. These data suggest macrophages at the site of insult play a dual role in the generation and prevention of pain.…”

Section: Introductionmentioning

confidence: 99%

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The impact of sex and physical activity on the local immune response to muscle pain

Lesnak

Hayashi

Plumb

et al. 2022

Preprint

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Induction of muscle pain triggers a local immune response to produce pain and this mechanism may be sex and activity level dependent. The purpose of this study was to measure the immune system response in the muscle following induction of pain in sedentary and physically active mice. Muscle pain was produced via an activity-induced pain model using acidic saline combined with fatiguing muscle contractions. Prior to induction of muscle pain, mice (C57/BL6) were sedentary or physically active (24hr access to running wheel) for 8 weeks. The ipsilateral gastrocnemius was harvested 24hr after induction of muscle pain for RNA sequencing or flow cytometry. RNA sequencing revealed activation of several immune pathways in both sexes after induction of muscle pain, and these pathways were attenuated in physically active females. Uniquely in females, the antigen processing and presentation pathway with MHC II signaling was activated after induction of muscle pain; activation of this pathway was blocked by physical activity. Blockade of MHC II attenuated development of muscle hyperalgesia exclusively in females. Induction of muscle pain increased the number of macrophages and T-cells in the muscle in both sexes, measured by flow cytometry. In both sexes, the phenotype of macrophages shifted toward a pro-inflammatory state after induction of muscle pain in sedentary mice (M1+M1/2) but toward an anti-inflammatory state in physically active mice (M2+M0). Thus, induction of muscle pain activates the immune system with sex-specific differences in the transcriptome while physical activity attenuates immune response in females and alters macrophage phenotype in both sexes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Muscle Pain and Immune Cellsmentioning

confidence: 51%

Section: Impact Of Prior Physical Activity On Immune Mechanismsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The impact of sex and physical activity on the local immune response to muscle pain

Lesnak

Hayashi

Plumb

et al. 2022

Preprint

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Neuroimmune Mechanisms Underlying Post-acute Sequelae of SARS-CoV-2 (PASC) Pain, Predictions from a Ligand-Receptor Interactome

2023

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Purpose of Review Individuals with post-acute sequelae of SARS-CoV-2 (PASC) complain of persistent musculoskeletal pain. Determining how COVID-19 infection produces persistent pain would be valuable for the development of therapeutics aimed at alleviating these symptoms. Recent Findings To generate hypotheses regarding neuroimmune interactions in PASC, we used a ligand-receptor interactome to make predictions about how ligands from PBMCs in individuals with COVID-19 communicate with dorsal root ganglia (DRG) neurons to induce persistent pain. In a structured literature review of -omics COVID-19 studies, we identified ligands capable of binding to receptors on DRG neurons, which stimulate signaling pathways including immune cell activation and chemotaxis, the complement system, and type I interferon signaling. The most consistent finding across immune cell types was an upregulation of genes encoding the alarmins S100A8/9 and MHC-I. Summary This ligand-receptor interactome, from our hypothesis-generating literature review, can be used to guide future research surrounding mechanisms of PASC-induced pain.

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The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPARγ Receptors

et al. 2022

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Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPARγ, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPARγ-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPARγ in macrophages.

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Regular swimming exercise prevented the acute and persistent mechanical muscle hyperalgesia by modulation of macrophages phenotypes and inflammatory cytokines via PPARγ receptors

Cited by 11 publications

References 68 publications

The impact of sex and physical activity on the local immune response to muscle pain

The impact of sex and physical activity on the local immune response to muscle pain

Neuroimmune Mechanisms Underlying Post-acute Sequelae of SARS-CoV-2 (PASC) Pain, Predictions from a Ligand-Receptor Interactome

The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPARγ Receptors

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