The macrophage: a key player in the pathophysiology of peripheral neuropathies

Abstract

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

Anti-Inflammatory Activity of Synaptamide in the Peripheral Nervous System in a Model of Sciatic Nerve Injury

“…CD163 is a member of the scavenger receptor cysteine-rich family and is expressed by anti-inflammatory M2 macrophages, which produce anti-inflammatory cytokines and opioid peptides that are important for neuropathic pain reduction [ 29 , 30 ]. At day 14 after the surgery, CD163 immunoreactivity was significantly increased in both groups that underwent the chronic constriction injury, in comparison to the “Sham” (5.6 ± 0.6%, p < 0.001) and “Sham + Syn” (4.0 ± 0.5%, p < 0.001) groups ( Figure 3 C,F).…”

Iron Metabolism and Ferroptosis in Peripheral Nerve Injury

“…During the Wallerian degeneration, activation of SCs is accompanied by recruitment of immune cells into the lesion site such as lymphocytes, macrophages and neutrophils [98]. Among these different cells, macrophages not only play a key role in promoting SCs activation and removing myelin debris but also contributing to the creation of permissive environment for axonal regeneration by releasing different proregenerative factors such as growth factors, chemokines, cytokines, and extracellular matrix (ECM) molecules [99]. In addition, macrophages-derived endosomes also play a crucial role in the Wallerian degeneration and axonal regeneration [100].…”

Autologous Platelet-Rich Growth Factor Reduces M1 Macrophages and Modulates Inflammatory Microenvironments to Promote Sciatic Nerve Regeneration

“…The success of peripheral nerve regeneration relies on both neuronal and non-neuronal cells, such as macrophages [ 1 , 2 ]. Damaged Schwann cells (SCs) and axons secrete chemo-attractive factors, TNFα and IL-1β, for the recruitment of macrophages [ 3 ].…”