Macrophage roles in peripheral nervous system injury and pathology: Allies in neuromuscular junction recovery
Introduction
Insults to the peripheral nervous system (PNS) are common and can be debilitating. Over 2% of patients with limb trauma suffer peripheral nerve injuries (Padovano et al., 2020). These injuries often have long term detrimental effects on quality of life, with 30% of patients with work-related nerve injuries suffering permanent disabilities (Akel et al., 2013; Bergmeister et al., 2020). Nerve-related injuries also have a high financial burden. Traumatic injuries to the brachial plexus, for example, are estimated to incur over $1.1 million in indirect costs per patient (Hong et al., 2019). Degenerative neuromuscular diseases, while rarer, have devastating effects on the PNS. Neuromuscular diseases can cause temporary or permanent paralysis, which can be life-threatening. Amyotrophic lateral sclerosis (ALS), for example, affects approximately 5 in 100,000 people in the United States (Mehta et al., 2014) and is characterized by an ultimately fatal progressive paralysis, with only 7% of patients surviving 5 years after diagnosis (del Aguila et al., 2003). Understanding the processes underlying PNS damage—from either traumatic or neurodegenerative etiologies—and optimizing repair is critical to reducing the morbidity and mortality associated with peripheral nerve injuries and neuromuscular diseases.
The body's response to PNS nerve damage involves multiple cell types, including axonal Schwann cells (SCs), terminal (perisynaptic) Schwann cells (tSCs), endothelial cells, and immune cells such as macrophages, neutrophils, and T-cells. tSCs are non-myelinating glial cells that reside at the neuromuscular junction (NMJ) and perform a wide variety of roles, including maintaining NMJ structure (Reddy et al., 2003), phagocytosing nerve debris after injury (Duregotti et al., 2015), and facilitating endplate reinnervation (Son and Thompson, 1995; Kang et al., 2003). Endothelial cells associated with blood vessels increase in number with angiogenesis and guide myelinating SCs, which then guide regenerating axons, across a nerve injury site (Cattin et al., 2015). Immune cells mount inflammatory responses to PNS insults and perform a variety of other roles, including clearing cellular debris and secreting factors integral to regeneration, including vascular endothelial growth factor (VEGF), a key regulator of angiogenesis (Lu et al., 2020).
Peripheral nerve damage ultimately disrupts the NMJ, causing functional muscle denervation. The NMJ is where an axon terminal contacts a motor endplate (Fig. 1) and is critical for muscle function. The axon terminal releases acetylcholine, which binds to receptors on the motor endplate to cause muscle contraction (Dale et al., 1936; Fertuck and Salpeter, 1974). Mechanisms of denervation and reinnervation at the level of the synapse have been understudied; however, they are critically important. When a nerve is damaged, the distal segment of the axon beyond the injury degenerates, and the nerve endings that once innervated NMJs are lost. If axons grow across the injury site but do not properly reinnervate NMJs, motor improvement will be limited. NMJ reinnervation is vital for regaining muscle function. Additionally, functional recovery is positively correlated with completely reinnervated NMJs (Vannucci et al., 2019). NMJ disturbances are central to the development of neuromuscular diseases as well. ALS (Fischer et al., 2004), spinal muscular atrophy (SMA) (Swoboda et al., 2005), and Guillain-Barré syndrome (GBS) (Ho et al., 1997) can all result in denervation at the level of the NMJ. In ALS rodent models, therapies that rescue lower motor neurons but fail to protect NMJs do not improve lifespan (Suzuki et al., 2007); reviewed in (Murray et al., 2010). It is clear that treatment and research strategies focused only at the motor neuron or axonal regeneration are incomplete; understanding degenerative and regenerative processes at the NMJ is vital to improving recovery after injury and disease.
The immune response is important for axonal regeneration at the nerve injury site and also occurs downstream in the muscle, where is integral to NMJ reinnervation. Changes in monocyte/macrophage activity at the NMJ have been observed after PNS insults, including peripheral nerve injuries (Jablonka-Shariff et al., 2020), ALS (Van Dyke et al., 2016; Trias et al., 2017), and SMA (Dachs et al., 2011). Macrophages are an incredibly diverse cell type; they can both stimulate and control inflammation and they have the capacity to promote nerve repair. They are known to phagocytose debris of necrotic tissue fragments (Mueller et al., 2001), secrete growth factors (Tomlinson et al., 2018; Bombeiro et al., 2018), promote angiogenesis (Cattin et al., 2015), and interact with tSCs and immune cells (Lu et al., 2020; Savage et al., 2008). Unfortunately, their role at the NMJ in peripheral nerve injury has received less investigative focus. While nerve injuries are distinct from other PNS insults like ALS, SMA, and GBS, all of these pathologies ultimately converge on the functional denervation of the NMJ and consequent paralysis. Evaluating macrophage roles at the NMJ in multiple types of PNS damage provides a more complete picture of macrophage activity in the PNS and may yield insights as to their activity in nerve injuries. In this review, we discuss macrophage roles in PNS pathologies with a focus on the NMJ.
Section snippets
Macrophage types and function
Classifying macrophage phenotypes allows us to predict their behavior, relate their activity to other pathologies, and potentially influence their activity. Macrophages come in two classes, tissue-resident and infiltrating (Griffin and George, 1993). Tissue-resident macrophages are present in peripheral nerves under homeostatic conditions, and can proliferate following injury or infection. Monocytes, which differentiate into macrophages, circulate in the blood and infiltrate damaged tissues. It
Macrophages after nerve injury
Macrophages have been well-studied at the nerve injury site and are vital to nerve regeneration (Cattin et al., 2015; Barrette et al., 2008; Brück et al., 1996); reviewed in (Zigmond and Echevarria, 2019; Liu et al., 2019). After nerve transection, the distal nerve segment rapidly degenerates in a process called Wallerian degeneration. Endoneurial macrophages express CCL7, which attracts both M1 and M2 macrophages to the injury site (Ydens et al., 2020; Xuan et al., 2015). Infiltrating
Macrophages and NMJ disease
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive paralysis as upper and lower motor neurons die. The NMJ is pivotal in the development of ALS. Denervation at the level of the NMJ precedes motor neuron loss and symptom development and worsens as symptoms progress (Fischer et al., 2004; Van Dyke et al., 2016). The role of macrophages in ALS progression is complex; they seem to be protective in early stages and degenerative in later stages. Enlarged
Conclusion
It has become apparent in recent years that macrophages are an essential component of nerve injury and regeneration. Their significance has been demonstrated at the injury site and in denervating disease pathology. The negative connotation associated with macrophages and inflammation is slowly changing as evidence emerges demonstrating non-detrimental functions of macrophages in disease. For nerve repair research, a new picture has developed, demonstrating the influence of both pro- and
Grant support
Supported by the NIH National Institute of Neurological Disorders and Stroke K08NS096232 (to A.K.S.W.) and the NIH National Heart Lung Blood Institute training grant 5 T35 HL 7815-25 (to R.R.).
Declaration of competing interest
None.
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2022, Experimental NeurologyCitation Excerpt :Generally, there are at least three potential sources of origin conceivable, like proliferation of “remaining/surviving” endoneurial macrophages, monocytic influx and a possible origin from the epineurial compartment as it may occur after peripheral nerve injury (Amann and Prinz, 2020; Arvidson, 1977; Gaudet et al., 2011; Klein and Martini, 2016; Mueller et al., 2001; Stoll and Muller, 1999; Ydens et al., 2020). Along these lines it may also be important to consider presynaptic integrity and preserved grip strength as being related to macrophages at the NMJ (Rios et al., 2021), a so far under-researched field. Based on our unpublished observations, we found only very few macrophages (in the range of 1.5% - 3.5%) in the vicinity of NMJs of P0het mice (unpublished observations).
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