IRF2 exacerbates diabetic neuropathic pain by promoting high glucose-induced M1 polarization through IL-6/STAT3.

BACKGROUND: M1 macrophage polarization is a key mechanism in diabetic neuropathic pain (DNP), and interferon regulatory factor 2 (IRF2) has been shown to regulate macrophage polarization. OBJECTIVE: The present study investigated whether IRF2 participates in DNP progression by regulating macrophage polarization. METHODS: A DNP mouse model was established using a high-fat diet combined with streptozotocin (STZ), and an in vitro model of RAW264.7 macrophages stimulated with high glucose (HG) was used for parallel validation. The metabolic status of the mice was assessed by regular monitoring of body weight and fasting blood glucose levels. Pathological damage to the sciatic nerve was detected via HE staining. Pain sensitivity was comprehensively evaluated using von Frey tests and hot plate experiments. Western blot, immunofluorescence, ELISA, and RT‒qPCR analyses were used to detect protein and gene expression. RESULTS: IRF2 was highly expressed in DNP mice and HG-stimulated RAW264.7 macrophages. Knockdown of IRF2 improved pain sensitivity in DNP mice (increased tactile response thresholds and decreased thermal response latency) and ameliorated sciatic nerve injury. Additionally, IRF2 knockdown suppressed M1 macrophage polarization (reduced expression of iNOS, CD80, and CD86) and inflammatory responses (lowered IL-1β, IL-6, and TNF-α levels). Further, IRF2 promoted p-STAT3/STAT3 expression, and treatment with colivelin, a STAT3 activator, attenuated the inhibitory effect of IRF2 knockdown on M1 polarization. Moreover, IRF2 was demonstrated to bind to the IL-6 promoter and increase its transcriptional activity. CONCLUSIONS: IRF2 exacerbates DNP by activating IL-6/STAT3 to promote HG-induced M1 macrophage polarization.