Abstract
BackgroundInflammatory molecular signals are modulated by a variety of intracellular transduction pathways, the activation of which may induce and amplify the spread of inflammatory response. Suppresser of cytokine signaling 3 (SOCS3) is an established negative feedback regulation transcription factor associated with tumor, diabetes mellitus, inflammation and anaphylaxis. Herein, we investigated whether SOCS3 in the paraventricular nucleus (PVN) can attenuate pro-inflammatory responses, and thereby relieve the inflammatory pain.MethodsAdeno-associated virus (AAV) overexpressing SOCS3 was pre-injected into the PVN. Three weeks later, rat model of chronic inflammatory pain was established via subcutaneous injection of complete Freund’s adjuvant (CFA) into the plantar center of hind paws. The therapeutic effect of SOCS3 was tested by the measurement of thermal and mechanical allodynia. In mechanistic study, the protein level of SOCS3 was evaluated by Western blotting, and the expression of c-fos and Iba-1 were assessed by immunofluorescent staining.ResultsInflammatory pain was associated with upregulated interleukin 6 (IL-6) and SOCS3 in PVN in the acute phase. Thermal hyperalgesia can be relieved by intra-PVN injection of IL-6 neutralizing antibody (NA). Meanwhile, the upregulated c-fos and microglial activation was reversed. Furthermore, SOCS3 expression in PVN was downregulated in the chronic phase. Intra-PVN injection of AAV overexpressing SOCS3 suppressed the activation of neurons and attenuated thermal hyperalgesia and mechanical allodynia.ConclusionInhibition of IL-6 signaling attenuated inflammatory hyperalgesia in the acute phase. SOCS3 overexpression in the PVN attenuated inflammatory pain in the chronic phase via suppression of neuronal activation.
Highlights
Inflammatory molecular signals are modulated by a variety of intracellular transduction pathways, the activation of which may induce and amplify the spread of inflammatory response
The effects of intra-paraventricular nucleus (PVN) injection of interleukin 6 (IL-6) neutralizing antibody on the inflammatory pain in acute phase in rats To investigate the function of IL-6 in the acute phase of inflammatory pain, rats underwent subcutaneous injection of complete Freund’s adjuvant (CFA), and 1 day thereafter micro-injection of IL-6 neutralizing antibody into PVN, with thermal pain threshold recorded at post-micro-injection 40 min, 2 h, 4 h, 6 h and 8 h, respectively
IL-6 neutralizing antibody group presented a notable decrease in Iba-1 labeling in PVN (Fig. 2c)
Summary
Inflammatory molecular signals are modulated by a variety of intracellular transduction pathways, the activation of which may induce and amplify the spread of inflammatory response. We investigated whether SOCS3 in the paraventricular nucleus (PVN) can attenuate pro-inflammatory responses, and thereby relieve the inflammatory pain. Meng et al Journal of Inflammation (2020) 17:12 regulator suppressor of cytokine signaling (SOCS) proteins are secreted to inhibit pro-inflammatory cytokine signals [8]. As a significant member of the SOCS family, SOCS3 can modulate the innate and adaptive immune responses by regulating the extent and duration of cytokine-induced signaling. Exogenous administration of SOCS proteins can compensate for the degradative loss of endogenous SOCS3 and terminate noxious cytokine signaling during an acute inflammatory response [14]
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