IL-10 Cytokine Released from M2 Macrophages Is Crucial for Analgesic and Anti-inflammatory Effects of Acupuncture in a Model of Inflammatory Muscle Pain

Silva, Morgana Duarte da; Bobinski, Franciane; Sato, Karina Laurenti; Kolker, Sandra J.; Sluka, Kathleen A.; Santos, Adair R.S.

doi:10.1007/s12035-014-8790-x

Cited by 133 publications

(99 citation statements)

References 58 publications

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“…Specifically we show the following findings: (1) depletion of resident macrophages and blockade of TLR4 receptors in muscle attenuated the development of bilateral mechanical hyperalgesia induced by repeated acid saline injection; (2) replacement of a one acid injection by LPS to directly activate resident macrophages, or the inflammatory cytokine IL-6 to mimic macrophage activation, induces bilateral mechanical hyperalgesia in a dose-dependent manner mimicking the effect of repeated acid injections; (3) Acidic pH, LPS and IL-6 increase the number of macrophages in muscle tissue, and acidic pH and LPS induce release of cytokines from peritoneal macrophages. Thus, these data extend prior studies which macrophages are important in fatigue-induced and inflammatory muscle pain [10;18], and suggest that acidic saline in muscle activates macrophages involving TLR4 receptors, and induces release of inflammatory cytokines to produce hyperalgesia.…”

Section: Discussionsupporting

confidence: 87%

Resident Macrophages in Muscle Contribute to Development of Hyperalgesia in a Mouse Model of Noninflammatory Muscle Pain

Gong

Abdelhamid

Carvalho

et al. 2016

The Journal of Pain

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Macrophages play a role in innate immunity within the body, are located in muscle tissue, and can release inflammatory cytokines that sensitize local nociceptors. Here we investigate the role of resident macrophages in the non-inflammatory muscle pain model induced by 2 pH 4.0 injections 5 days apart in the gastrocnemius muscle. We demonstrate that injecting 2 pH 4.0 injections into the gastrocnemius muscle increased the number of local muscle macrophages, and depleting muscle macrophages with clodronate liposomes prior to acid injections attenuated the hyperalgesia produced by this model. To further examine the contribution of local macrophages to this hyperalgesia, we injected mice intramuscularly with C34, a TLR4 receptor antagonist. When given before the first pH 4.0 injection, C34 attenuated the muscle and tactile hyperalgesia produced by the model. However, when given before the second injection C34 had no effect on the development of hyperalgesia. Then to test whether activation of local macrophages sensitizes nociceptors to normally non-nociceptive stimuli we replaced either the first or second acid injection with the immune cell activator lipopolysaccharide (LPS), or the inflammatory cytokine interleukin-6 (IL-6). Injecting LPS or IL-6 instead of the either the first or second pH 4.0 injection resulted in a dose-dependent increase in paw withdrawal responses and decrease in muscle withdrawal thresholds. The highest doses of LPS and IL-6 resulted in development of hyperalgesia bilaterally. The present study shows that resident macrophages in muscle are key to development of chronic muscle pain.

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Section: Discussionsupporting

confidence: 87%

Resident Macrophages in Muscle Contribute to Development of Hyperalgesia in a Mouse Model of Noninflammatory Muscle Pain

Gong

Abdelhamid

Carvalho

et al. 2016

The Journal of Pain

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“…This is consistent with the lack of changes on baseline mechanical nociceptive threshold in skin [47] or muscle [15] in IL-10 knockout mice, or after administration of IL-10R blocking antibodies to control mice [27]. Conversely, administration of systemic recombinant IL-10 [27] or intrathecal viral vectors encoding IL-10 [33,34] do not change baseline nociceptive mechanical threshold in control rodents, nor the mechanosensitivity of C-fibers from mice recorded in vitro [22].…”

Section: Discussionsupporting

confidence: 85%

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

Álvarez

Bogen

Green

et al. 2017

PAIN

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Delayed-onset muscle soreness is typically observed after strenuous or unaccustomed eccentric exercise. Soon after recovery, blunted muscle soreness is observed on repeated eccentric exercise, a phenomenon known as repeated bout effect (RBE). Although regular physical activity decreases muscle hyperalgesia, likely because of increased production of the anti-inflammatory cytokine interleukin-10 (IL-10) in the skeletal muscle, whether IL-10 also contributes to the antinociceptive effect of RBE is unknown. Furthermore, whether IL-10 attenuates muscle hyperalgesia by acting on muscle nociceptors remains to be established. Here, we explored the hypothesis that blunted muscle nociception observed in RBE depends on a local effect of IL-10, acting on IL-10 receptor 1 (IL-10R1) expressed by muscle nociceptors. Results show that after a second bout of eccentric exercise, rats exhibited decreased muscle hyperalgesia, indicative of RBE, and increased expression of IL-10 in the exercised gastrocnemius muscle. Although knockdown of IL-10R1 protein in nociceptors innervating the gastrocnemius muscle by intrathecal antisense oligodeoxynucleotide did not change nociceptive threshold in naive rats, it unveiled latent muscle hyperalgesia in rats submitted to eccentric exercise 12 days ago. Furthermore, antisense also prevented the reduction of muscle hyperalgesia observed after a second bout of eccentric exercise. These data indicate that recovery of nociceptive threshold after eccentric exercise and RBE-induced analgesia depend on a local effect of IL-10, acting on its canonical receptor in muscle nociceptors.

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“…These M2 macrophages, in turn, reduce muscle pain and inflammation induced by carrageenan in an IL‐10‐dependent manner (da Silva et al . ).…”

Section: Discussionmentioning

confidence: 97%

Interleukin‐10 limits intense acute swimming‐induced muscle mechanical hyperalgesia in mice

Borghi

Pinho‐Ribeiro

Zarpelon

et al. 2015

Experimental Physiology

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New Findings r What is the central question of this study?This study investigated the role of the endogenous anti-inflammatory cytokine interleukin-10 in intense acute swimming-induced muscle mechanical hyperalgesia in mice. r What is the main finding and its importance?Endogenous interleukin-10 has a key role in limiting exercise-induced muscle pain in a model presenting similarities to delayed-onset muscle soreness in mice. Interleukin-10 reduced muscle pain by diminishing leucocyte recruitment, hyperalgesic cytokine production, oxidative stress and myocyte damage. Interleukin-10 (IL-10) is an antihyperalgesic cytokine. In this study, IL-10-deficient (IL-10−/− ) mice were used to investigate the role of endogenous IL-10 in intense acute swimming-induced muscle mechanical hyperalgesia, which presents similarities with delayed-onset muscle soreness. An intense acute swimming session of 1 or 2 h induced significant muscle mechanical hyperalgesia in a time-dependent manner in wild-type mice compared with the sham group 24 h after the session, which was further increased in IL-10 −/− mice (P ˂ 0.05). Intraperitoneal treatment of wild-type mice with IL-10 (1-10 ng) reduced muscle mechanical hyperalgesia in a dose-dependent manner and reversed the enhanced muscle hyperalgesia in IL-10 −/− mice (P ˂ 0.05). The 2 h swimming session induced increases in tumour necrosis factor-α, interleukin-1β and IL-10 production in the soleus muscle. However, tumour necrosis factor-α and interleukin-1β production in the soleus muscle were even higher in IL-10 −/− mice between 2 and 6 h after the stimulus (P ˂ 0.05). There was no statistical difference in the levels of the antihyperalgesic cytokines interleukin-4, interleukin-5, interleukin-13 and transforming growth factor-β between wild-type and IL-10 −/− mice (P ˃ 0.05). Interleukin-10 deficiency also resulted in increased myeloperoxidase activity, greater depletion of reduced glutathione levels, increased superoxide anion production and the maintenance of high plasma concentrations of creatine kinase (until 24 h after the swimming session) in soleus muscle (P ˂ 0.05). These results demonstrate that endogenous IL-10 controls intense acute swimming-induced muscle mechanical hyperalgesia by limiting oxidative stress and cytokine production.

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IL-10 Cytokine Released from M2 Macrophages Is Crucial for Analgesic and Anti-inflammatory Effects of Acupuncture in a Model of Inflammatory Muscle Pain

Cited by 133 publications

References 58 publications

Resident Macrophages in Muscle Contribute to Development of Hyperalgesia in a Mouse Model of Noninflammatory Muscle Pain

Resident Macrophages in Muscle Contribute to Development of Hyperalgesia in a Mouse Model of Noninflammatory Muscle Pain

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

Interleukin‐10 limits intense acute swimming‐induced muscle mechanical hyperalgesia in mice

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