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Macrophages are present in all mammalian tissues and coexist with various cell types in order to respond to different environmental cues. However, the role of these cells has been underestimated in the context of peripheral nerve damage. More importantly, macrophages display divergent characteristics, associated with their origin, and in response to the modulatory effects of their microenvironment. Interestingly, the advent of new techniques such as fate mapping and single-cell transcriptomics and their synergistic use has helped characterize in detail the origin and fate of tissue-resident macrophages in the peripheral nervous system (PNS). Furthermore, these techniques have allowed a better understanding of their functions from simple homeostatic supervisors to chief regulators in peripheral neuropathies. In this review, we summarize the latest knowledge about macrophage ontogeny, function and tissue identity, with a particular focus on PNS-associated cells, as well as their interaction with reactive oxygen species under physiological and pathological conditions. We then revisit the process of Wallerian degeneration, describing the events accompanying axon degeneration, Schwann cell activation and most importantly, macrophage recruitment to the site of injury. Finally, we review these processes in light of internal and external insults to peripheral nerves leading to peripheral neuropathies, the involvement of macrophages and the potential benefit of the targeting of specific macrophages for the alleviation of functional defects in the PNS. Graphical Abstract

Curcumin was shown to exert beneficial effects on nerve function in peripheral neuropathies. Despite its prominent biological activities, curcumin presents with unfavorable pharmacokinetics. For this purpose, we have developed curcumin-loaded cyclodextrin/cellulose nanocrystals (NanoCur) to bypass this limitation. The current study aims to assess the potency of NanoCur in Charcot-Marie-Tooth disease type 1A (CMT1A) rodent models and compare its efficacy to Theracurmin® (Thera), a commercially available curcumin formulation, while elaborating on its mechanism of action. For that, a low dose of NanoCur was chronically administered for rodents and CMT1A neuropathology was assessed through a battery of functional, histological and biochemical tests. Toxicity and mechanism of action of NanoCur were evaluated both in-vivo & in-vitro. The overall study supports an improved motor function, associated with an amelioration in peripheral myelination in the NanoCur, but not Thera-treated CMT1A animals, combined to a high margin of safety. Furthermore, NanoCur appears to perform its effect through an alleviation of inflammatory pathways, involving macrophage recruitment to the diseased nerve. This study shows that NanoCur associates with therapeutic benefits at the cellular and functional levels in CMT1A with minimal systemic toxicity, promoting it as a potential therapeutic candidate for CMT1A disease and, possibly, other forms of neuropathy.

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