Low-Dose Pulsatile Interleukin-6 As a Treatment Option for Diabetic Peripheral Neuropathy

Abstract

Diabetic peripheral neuropathy (DPN) remains one of the most common and serious complications of diabetes. Currently, pharmacological agents are limited to treating the pain associated with DPN, and do not address the underlying pathological mechanisms driving nerve damage, thus leaving a significant unmet medical need. Interestingly, research conducted using exercise as a treatment for DPN has revealed interleukin-6 (IL-6) signaling to be associated with many positive benefits such as enhanced blood flow and lipid metabolism, decreased chronic inflammation, and peripheral nerve fiber regeneration. IL-6, once known solely as a pro-inflammatory cytokine, is now understood to signal as a multifunctional cytokine, capable of eliciting both pro- and anti-inflammatory responses in a context-dependent fashion. IL-6 released from muscle in response to exercise signals as a myokine and as such has a unique kinetic profile, whereby levels are transiently elevated up to 100-fold and return to baseline levels within 4 h. Importantly, this kinetic profile is in stark contrast to long-term IL-6 elevation that is associated with pro-inflammatory states. Given exercise induces IL-6 myokine signaling, and exercise has been shown to elicit numerous beneficial effects for the treatment of DPN, a causal link has been suggested. Here, we discuss both the clinical and preclinical literature related to the application of IL-6 as a treatment strategy for DPN. In addition, we discuss how IL-6 may directly modulate Schwann and nerve cells to explore a mechanistic understanding of how this treatment elicits a neuroprotective and/or regenerative response. Collectively, studies suggest that IL-6, when administered in a low-dose pulsatile strategy to mimic the body’s natural response to exercise, may prove to be an effective treatment for the protection and/or restoration of peripheral nerve function in DPN. This review highlights the studies supporting this assertion and provides rationale for continued investigation of IL-6 for the treatment of DPN.

Involvement of microRNA-146a in diabetic peripheral neuropathy through the regulation of inflammation

“…The inflammatory response is likely critical for the development and progression of DPN, despite the existence of various other acceptable pathogenetic factors, which may explain the nerve damage observed in DPN rats. 17 In recent years, studies have shown that TNF-α is closely related to DPN and is upregulated in the sciatic nerve of DPN rats. 18 The upregulation of TNF-α promotes a series of downstream inflammatory responses, which leads to damage and demyelination of the nerve cells, resulting in the final peripheral nerve dysfunction.…”

Systemic Factors During Metabolic Disease Progression Contribute to the Functional Decline of Adipose Tissue-Derived Mesenchymal Stem Cells in Reproductive Aged Females

“…The observed association between serum IL6 concentrations and ADSCs proliferation is consistent with previous studies highlighting the importance of IL6 in the maintenance and growth of mesenchymal stem cells (Pricola et al, 2009; van de Vyver et al, 2016). The mechanism of which is most likely related to the pleiotropic effects of IL6 capable of eliciting both a pro- and anti-inflammatory response depending on the environmental context (Cox et al, 2017). Classical IL6 signaling is mediated through the association of the protein-bound receptor complex (IL6 + IL6R) with the gp130 receptor subunit and elicits an anti-inflammatory protective effect (Rose-John, 2012, 2017).…”

Current Therapeutic Strategies in Diabetic Foot Ulcers

“…On the other hand, the use of biological therapy with low doses of IL-6 has been demonstrated to promote improvement of blood flow, decrease chronic inflammation, and regenerate peripheral nerve fibers. Accordingly, IL-6 may prove to be an effective treatment for the protection and/or restoration of peripheral nerve function in DPN [50]; see Table 1.…”