The Role of the IL-4 Signaling Pathway in Traumatic Nerve Injuries

Abstract

Following traumatic peripheral nerve injury, adequate restoration of function remains an elusive clinical goal. Recent research highlights the complex role that the immune system plays in both nerve injury and regeneration. Pro-regenerative processes in wounded soft tissues appear to be significantly mediated by cytokines of the type 2 immune response, notably interleukin (IL)-4. While IL-4 signaling has been firmly established as a critical element in general tissue regeneration during wound healing, it has also emerged as a critical process in nerve injury and regeneration. In this context of peripheral nerve injury, endogenous IL-4 signaling has recently been confirmed to influence more than leukocytes, but including also neurons, axons, and Schwann cells. Given the role IL-4 plays in nerve injury and regeneration, exogenous IL-4 and/or compounds targeting this signaling pathway have shown encouraging preliminary results to treat nerve injury or other neuropathy in rodent models. In particular, the exogenous stimulation of the IL-4 signaling pathway appears to promote postinjury neuron survival, axonal regeneration, remyelination, and thereby improved functional recovery. These preclinical data strongly suggest that targeting IL-4 signaling pathways is a promising translational therapy to augment treatment approaches of traumatic nerve injury. However, a better understanding of the type 2 immune response and associated signaling networks functioning within the nerve injury microenvironment is still needed to fully develop this promising therapeutic avenue.

Development of a polyacrylamide/chitosan composite hydrogel conduit containing synergistic cues of elasticity and topographies for promoting peripheral nerve regeneration

“…These results suggested that the PAM/CS hydrogel conduits containing synergistic cues of elasticity and topography could promote the proliferation of SCs and guide axon regrowth during regeneration. 40…”

The Immunological Roles of Olfactory Ensheathing Cells in the Treatment of Spinal Cord Injury

“…Nevertheless, implanted OECs in the lesioned spinal cord tissue are likely to interact with these cells to regulate inflammation. Secreted anti-inflammatory cytokines, such as IL-4, IL-10, and TGF-β, are capable of modulating the inflammatory response, resulting in a decrease in the production of several pro-inflammatory factors such as IL-1β, TNF-α and IL-6, by microglia/macrophages ( 143 , 157 , 158 ). Moreover, these cytokines also reduce infiltration of immunocytes, such as macrophages, neutrophils, and monocytes, into inflammatory lesions in the spinal cord by downregulating chemokines in vivo , thereby effectively attenuating subsequent inflammation ( 159 , 160 ).…”

“…Once OECs are implanted into the injured spinal cord zone, numerous molecules released from OECs, as acute positive and negative regulators participate in modulating the expression and activity of cytokines and chemokines ( 167 ). For instance, the anti-inflammatory cytokines IL-4, IL-10, TGF-β, and IL-13 produced by OECs protect against cell degeneration or death by modulating iNOS and NO production in the context of LPS/IFN-γ stimulation ( 90 , 158 , 159 , 161 ). Meanwhile, these anti-inflammatory cytokines are indicative of inhibition of the release of the pro-inflammatory cytokines TNF-α, IL-1β, IL-2, and IL-6 ( 161 , 165 ).…”

Neurotrophic and immunomodulatory effects of olfactory ensheathing cells as a strategy for neuroprotection and regeneration

“…OECs also release several signaling molecules, such as TNF and IL-1β, to recruit macrophages, thus modulating inflammation and neurodegeneration ( 14 , 44 , 59 ). In this context, OECs could modulate microglia-astrocyte responses by secreting anti-inflammatory cytokines such as IL-4, IL-10, IL-13 and TGF-β, capable to downregulate the pro-inflammatory factors IL-1β, TNF and IL-6 ( Figure 2 ) ( 60 – 62 ). A recent study showed that IL-1α and IL-1β, which are significantly involved in inflammatory responses, were down-regulated after OEC transplantation at the injury site.…”