Sensory neuron–associated macrophages as novel modulators of neuropathic pain

Abstract

The peripheral nervous system comprises an infinity of neural networks that act in the communication between the central nervous system and the most diverse tissues of the body. Along with the extension of the primary sensory neurons (axons and cell bodies), a population of resident macrophages has been described. These newly called sensory neuron–associated macrophages (sNAMs) seem to play an essential role in physiological and pathophysiological processes, including infection, autoimmunity, nerve degeneration/regeneration, and chronic neuropathic pain. After different types of peripheral nerve injury, there is an increase in the number and activation of sNAMs in the sciatic nerve and sensory ganglia. The activation of sNAMs and their participation in neuropathic pain development depends on the stimulation of pattern recognition receptors such as Toll-like receptors and Nod-like receptors, chemokines/cytokines, and microRNAs. On activation, sNAMs trigger the production of critical inflammatory mediators such as proinflammatory cytokines (eg, TNF and IL-1β) and reactive oxygen species that can act in the amplification of primary sensory neurons sensitization. On the other hand, there is evidence that sNAMs can produce antinociceptive mediators (eg, IL-10) that counteract neuropathic pain development. This review will present the cellular and molecular mechanisms behind the participation of sNAMs in peripheral nerve injury–induced neuropathic pain development. Understanding how sNAMs are activated and responding to nerve injury can help set novel targets for the control of neuropathic pain.

Macrophage as a Peripheral Pain Regulator

“…There is plenty of evidence that monocyte-derived infiltrating macrophages and tissueresident peripheral nerve macrophages are involved in neuropathic pain following surgical injury of the sciatic nerves or spinal nerves [15,44,50,94]. We have shown that L5 spinal nerve injury causes macrophage accumulation in L4 DRG, in which macrophage-derived HMGB1 induces RAGE-dependent transcriptional upregulation of Ca v 3.2 T-type Ca 2+ channels in nociceptors, leading to neuropathic pain [50].…”

“…The latter class of macrophages are present in tissues under homeostatic conditions. The bone marrow-derived infiltrating macrophages and tissue-resident macrophages have common and different roles in health and/or disease, and both of them are considered to participate in processing or modulation of pain signals [8,15]. The majority of tissues in the body contain tissue-resident macrophage populations that sense and respond to invading pathogens, environmental stressors or noxious stimuli, and are also essential in tissue development, homeostasis, remodeling and repair [16][17][18][19][20].…”

“…The heterogeneity is a necessary consequence of tissue-specific and microanatomical niche-specific functions during the development and tissue homeostasis. Apart from the well-described critical role of spinal microglia in the neuropathic and inflammatory pain, there is a growing body of evidence that "sensory neuron-associated macrophages", a subpopulation of resident peripheral nerve macrophages, participate in the development of peripheral nerve injury-induced neuropathic pain [12,14,15].…”

“…Neuropathic pain is caused by direct or indirect nerve damage or lesions in the neural circuitry that mediates pain, and involves a neuro-immune crosstalk [8,50,94,95]. Recent evidence indicates that peripheral nerve macrophages, a subpopulation of tissue-resident macrophages, originate primarily from late embryonic precursors and become replaced by bone marrow-derived macrophages over time (see Figure 1), and that monocyte-derived infiltrating macrophages following nerve injury can engraft in the pool of resident peripheral nerve macrophages, contributing to the development of neuropathic pain [12,15]. A number of mediators, such as ATP, SP, CCL2 and CX3CL1 derived from neurons, promote infiltration of adult monocyte-derived macrophages and/or proliferation of resident macrophages after nerve injury, leading to macrophage accumulation around nociceptors including the DRG [7,28,78,79,87,94] and then afterwards a variety of pro-nociceptive mediators derived from macrophages induce neuronal sensitization or excitation (Figure 2B).…”

“…There are a number of excellent review articles with respect to the role of spinal microglia and astrocytes in pathological pain elsewhere [9][10][11]. Intriguingly, the latest studies characterizing two subsets of tissue-resident macrophages, especially "peripheral nerve macrophages", originating from fetal and adult monocytes opened new avenue for understanding the role of peripheral macrophages as pain regulators [12][13][14][15]. Here, we focus on the role of peripheral infiltrating and tissue-resident macrophages in the development of somatic and visceral pathological pain including inflammatory and/or neuropathic components.…”