Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for diabetic neuropathic pain (DNP). This study aims to determine the role and mechanism of interleukin (IL)-35 in regulating microglial M1/M2 polarization in DNP. A rat model of DNP was induced by a single streptozocin injection and recombinant IL-35 (rIL-35) was then intrathecally administered to the rats for 14 days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured to assess the therapeutic effect of IL-35. Highly aggressive proliferating immortalized (HAPI), a rat microglia cell line, was treated with lipopolysaccharide (LPS) for M1 polarization or IL-4 for M2 polarization. The M1 markers (CD68, iNOS, TNF-α, IL-6) and M2 markers (CD206, Arg-1, IL-10) were examined. rIL-35 administration in DNP model rats elevated MWT and TWL, induced microglial polarization toward the M2 phenotype, suppressed JNK signaling and activated JAK2/STAT6 signaling. In vitro assay confirmed that rIL-35 induced microglial M2 polarization in HAPI cells through inhibiting JNK signaling and activating JAK2/STAT6 signaling. Collectively, the mechanism underlying therapeutic effect of IL-35 on DNP may relate to its promotion of microglial M2 polarization by regulating JNK signaling and JAK2/STAT6 signaling.

中文翻译：

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IL-35在糖尿病性神经性疼痛的大鼠模型中促进小胶质细胞M2极化。

将小胶质细胞极化从促炎性M1表型转换为消炎性M2表型代表了糖尿病性神经性疼痛（DNP）的新型治疗策略。本研究旨在确定白介素（IL）-35在调节DNP中小胶质细胞M1 / M2极化中的作用和机制。通过单次链脲佐菌素注射诱导DNP的大鼠模型，然后将鞘内施用IL-35（rIL-35）重组给大鼠。测量机械撤药阈值（MWT）和热撤药潜伏期（TWL）以评估IL-35的治疗效果。用脂多糖（LPS）处理M1极化或使用IL-4处理M2极化，将高侵袭性永生化（HAPI）大鼠小胶质细胞系进行处理。M1标记（CD68，iNOS，TNF-α，IL-6）和M2标记（CD206，Arg-1，检查IL-10）。在DNP模型大鼠中进行rIL-35给药可升高MWT和TWL，诱导小胶质细胞向M2表型极化，抑制JNK信号传导并激活JAK2 / STAT6信号传导。体外测定证实，rIL-35通过抑制JNK信号传导和激活JAK2 / STAT6信号传导诱导HAPI细胞中的小胶质细胞M2极化。总的来说，IL-35对DNP的治疗作用的潜在机制可能与其通过调节JNK信号传导和JAK2 / STAT6信号传导促进小胶质细胞M2极化有关。体外测定证实，rIL-35通过抑制JNK信号传导和激活JAK2 / STAT6信号传导诱导HAPI细胞中的小胶质细胞M2极化。总的来说，IL-35对DNP的治疗作用的潜在机制可能与其通过调节JNK信号传导和JAK2 / STAT6信号传导促进小胶质细胞M2极化有关。体外测定证实，rIL-35通过抑制JNK信号传导和激活JAK2 / STAT6信号传导诱导HAPI细胞中的小胶质细胞M2极化。总的来说，IL-35对DNP的治疗作用的潜在机制可能与其通过调节JNK信号传导和JAK2 / STAT6信号传导促进小胶质细胞M2极化有关。