Neuropathic pain, a debilitating condition with a prevalence of over 7% in the general population, poses a significant challenge in the field of medicine due to the lack of effective treatments. Recent research has shed light on the intricate molecular mechanisms underlying the development of neuropathic pain, particularly focusing on the neuroimmune cascade orchestrated by the ciliary neurotrophic factor (CNTF)-STAT3-interleukin-6 (IL-6) axis. This axis, activated in response to peripheral nerve damage, serves as a pivotal player in relaying immune signals across the Schwann cell-neuron-microglia network, contributing to the initiation and progression of neuropathic pain.
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Fig. 1 CNTF-STAT3-IL-6 axis mediates neuroinflammatory cascade across Schwann cell-neuron-microglia (Hu Z., et al. 2020).
The CNTF receptor complex, consisting of CNTR receptor (CNTFR), glycoprotein 130 (gp130), and leukemia inhibitory factor receptor (LIFR), acts as the gateway for CNTF signaling. In neurons, the expression of these receptors is significantly high, emphasizing their crucial role in mediating the signal cascade. The activation of STAT3, facilitated by the CNTF receptor complex, becomes evident in sensory neurons when exposed to sciatic nerve lysates. This activation, integral to the transcription program, is effectively blocked by ruxolitinib, a selective inhibitor of JAK1/2 downstream of the CNTFR complex. Furthermore, the downregulation of Cntfr, but not other receptors, underscores the specificity of the CNTF-CNTFR signal in STAT3 activation.
Simultaneously, IL-6, a well-known activator of STAT3, is implicated in microglia activation at the spinal dorsal horn. IL-6 is detected in regions where sensory neurons extend their bifurcated axons, emphasizing its role in mediating the central nervous system (CNS) neuroimmune cascade. Single-cell RNA sequencing analysis confirms the high expression of the IL-6 receptor (Il6ra) in microglia, strengthening the connection between IL-6 and microglial activation. Deletion of Il6ra in microglia results in reduced STAT3 activation post-injury, indicating the significance of IL-6 in mediating microglial responses.
The intricate interplay of the CNTF-STAT3-IL-6 axis is further highlighted in both acute (SNI) and chronic (CCI) nerve injury models. The study has shown that the deletion of Cntf, Wnt1aCre, Stat3fl/+, and Il6−/− mice results in decreased STAT3 activation and microgliosis in the spinal dorsal horn. This underscores the persistent involvement of the CNTF-STAT3-IL-6 axis in the neuroimmune response to varying degrees of nerve injury.
In addition to unraveling the molecular details of the immune cascade, researchers delve into the contribution of the CNTF-STAT3-IL-6 axis to the development of neuropathic pain. Genetic perturbations and pharmacological inhibition of this signaling axis effectively alleviate mechanical allodynia and heat hyperalgesia in a mouse model of neuropathic pain. The therapeutic implications are profound, suggesting that targeting the CNTF-STAT3-IL-6 axis could offer a potential avenue for pain management in neuropathic conditions.
The findings challenge the traditional view of CNTF solely as a neurotrophic factor and position it as a danger signal in response to nerve damage. However, the dynamic regulation of CNTF expression and release in response to injury remains an area of exploration. Understanding how CNTF senses and responds to peripheral insults is crucial for deciphering the initiation of the immune cascade.
In conclusion, the CNTF-STAT3-IL-6 axis emerges as a central player in the neuroimmune cascade associated with neuropathic pain. In peripheral injuries of the sensory nervous system, the CNTF protein, which is highly expressed by Schwann cells, activates STAT3 in neural axons, and STAT3 in turn translocates to the cytosol to initiate the transcription and expression of the cytokine IL-6 in sensory neurons. In turn, IL-6 is transported through sensory neurons to CNS projection areas and promotes the activation of microglia in the spinal cord. The inflammatory transmission process from the peripheral nervous system to the central nervous system via the CNTF-STAT3-IL-6-STAT3 signaling pathway across Schwann cells-sensory neurons-microglia promotes the development of neuropathic pain induced by peripheral nerve injury. Moreover, sensory neuron axons induced nociceptive sensitization after CNTF stimulation in an injury-independent manner. Thus, CNTF acts as a nervous system-specific "danger signal" molecule that performs the nervous system's function of sensing and responding to peripheral homeostasis by initiating a cascade of inflammatory processes induced by peripheral nerve injury in the central nervous system.
References
- Hu Z.; et al. CNTF-STAT3-IL-6 axis mediates neuroinflammatory cascade across Schwann cell-neuron-microglia. Cell Rports. 2020, 31(7).
- Kalpachidou T.; et al. Genetic and functional evidence for gp130/IL6ST-induced transient receptor potential ankyrin 1 upregulation in uninjured but not injured neurons in a mouse model of neuropathic pain. Pain. 2022, 163(3): 579.
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