Peripheral nerve injury induces the disconnection of axons from their cell bodies and leads to the disruption of axons and myelin sheaths in the injured nerve stumps as well as central chromatolysis and nuclear associated changes of somas. With the rapid development of genomics and proteomics, the global genetic and molecular characteristics in a wide variety of physiological and pathological conditions, including peripheral nerve injury and regeneration, were recognized. Many factors were also demonstrated to play fundamental roles in the repair and regeneration of injured peripheral nerves and thus were might be identified as prospective therapies for the treatment of peripheral nerve injury.
Differentially expressed cytokines in the injured SNs might essentially benefit the infiltration and polarization of monocytes, macrophages, and Schwann cells, encourage the phagocytosis and clearance of axon and myelin debris, and promote axon regrowth and regeneration. Actually, a large range of cytokines were found to be up-regulated in the injured nerve stumps. These cytokines might be secreted and released by Schwann cells and macrophages after peripheral nerve injury (18, 19). These up-regulated cytokines, including Ccl2, leukemia inhibitory factor (Lif), tumor necrosis factor-α (Tnf-α), interleukin-1α (Il-1α), interleukin-1β (I1-1β), and pancreatitis-associated protein III (Pap-III) recruit the infiltration of monocytes and macrophages into injured nerve sites and contribute to the remodeling and reconstruction of the microenvironment surrounding the injured sites (18, 20–23). In our current study, many other cytokines, including chemokine (C-C motif) ligand 12 (Ccl12), C-X-C motif chemokine ligand 2 (Cxcl2), and C-X-C motif chemokine ligand 3 (Cxcl3), were found to be particularly high-expressed in the injured nerve stumps after peripheral nerve injury, indicating the potential applications of these cytokines in treating peripheral nerve injury and promoting axon regeneration.
Moreover, it was worth noting that many cytokines might carry out opposing effects at multiple time points during peripheral nerve regeneration and represent a “double-edged sword” (11). Our current study suggested that differentially expressed upstream cytokines in the injured SNs after peripheral nerve injury were highly related with inflammation and immune responses. Therefore, the controversial biological roles of cytokines might be due to the degree and timing of inflammation and immune responses induced by different expression levels of cytokines (11). These results were also consistent with our previous finding that robust immune and inflammatory responses were sustained significantly involved during nerve degeneration and regeneration (24). These outcomes implied that, to achieve orchestrated regulation of cytokines, it was of great importance to obtain an overview of the expression patterns of cytokines in the injured nerve stumps at different time points after peripheral nerve injury.
Besides affecting the injured nerve stumps and reconstructing the regenerative microenvironment, cytokines could influence the expressions of neurotrophins and their receptors and thus could affect the neurite outgrowth of neurons (11). For instance, the addition of interleukin 4 (IL-4) or interferon-γ (IFN-γ) to neurotrophin-4 (NT-4)-treated DRG neurons would increase NT-4-induced neurite outgrowth and the addition of TNF-α to neurotrophin-treated DRG neurons would decrease neurotrophin-induced neurite outgrowth (25). In addition, cytokine induced inflammation and immune response would activate retrograde signaling and might induce the death or survival of DRG neurons (11, 26). Consequently, in our current study, we also jointly determine the dynamic expression levels of cytokines in DRGs and discovered some significantly changed cytokines, such as interferon alpha 4 (Ifna4), Il6, and interleukin 24 (Il24).
Interestingly, some cytokines, such as Cxcl10, were discovered to be up-regulated in nerve stumps but down-regulated in DRGs after nerve injury. It was shown that Cxcl10 could promote the invasion of lymphocytes and macrophages and affect myelination in a viral model of multiple sclerosis (27) and could induce neuropathic pain in DRGs after chronic constriction injury (28). Therefore, it was possible that up-regulated Cxcl10 in SNs after nerve injury could contribute to debris clearance in the injured nerve stumps while down-regulated Cxcl10 in DRGs could reduce neuropathic pain. Further functional studies would reveal the specific roles of these cytokines during peripheral nerve repair and regeneration and would provide new targets of the treatment of peripheral nerve injuries.