Related Experiment Video
Updated: Dec 26, 2025
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
IL-35 promotes microglial M2 polarization in a rat model of diabetic neuropathic pain
Yinghai Jiang1, Jing Wang1, Haiqin Li1
1Department of Pain, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China.
Abstract:
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.
Insights
Interleukin-35 (IL-35) alleviates diabetic neuropathic pain by shifting microglia from a pro-inflammatory M1 state to an anti-inflammatory M2 state. This involves regulating JNK and JAK2/STAT6 signaling pathways.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Diabetic neuropathic pain (DNP) is a debilitating condition.
- Microglial polarization plays a crucial role in DNP pathogenesis.
- Shifting microglia from M1 to M2 phenotype is a potential therapeutic strategy.
Purpose of the Study:
- To investigate the role of interleukin-35 (IL-35) in regulating microglial polarization in DNP.
- To elucidate the underlying molecular mechanisms of IL-35's therapeutic effects.
Main Methods:
- A rat model of DNP was established using streptozocin.
- Recombinant IL-35 (rIL-35) was administered intrathecally.
- Pain behaviors were assessed using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL).
- In vitro studies used a rat microglia cell line (HAPI) stimulated with LPS or IL-4.
- Microglial polarization markers and signaling pathways (JNK, JAK2/STAT6) were analyzed.
Main Results:
- Intrathecal rIL-35 administration significantly improved MWT and TWL in DNP rats.
- rIL-35 promoted microglial M2 polarization in vivo and in vitro.
- IL-35 suppressed JNK signaling and activated JAK2/STAT6 signaling in microglia.
- These signaling pathways were confirmed to mediate IL-35's effect on M2 polarization.
Conclusions:
- IL-35 exerts a therapeutic effect on DNP by promoting microglial M2 polarization.
- The mechanism involves the regulation of JNK and JAK2/STAT6 signaling pathways.
- IL-35 represents a promising therapeutic agent for DNP.
