Resident macrophages from dorsal root ganglia are important for the development of traumatic-induced neuropathic pain. In the first 5–7 days after a traumatic sciatic nerve injury (i.e., spinal nerve ligation (SNL), spared nerve injury (SNI), sciatic nerve transection or sciatic nerve ligation and transection), Ionized binding adapter protein 1 (Iba1) (+) resident macrophages cluster around dorsal root ganglia neurons, possibly contributing to nerve injury-induced hypersensitivity. Since infiltrating macrophages gradually recruited to the lesion site peak at about 7 days, the first few days post-lesion offer a window of opportunity when the contribution of Iba1 (+) resident macrophages to neuropathic pain pathogenesis could be investigated. Iba1 is an actin cross-linking cytoskeleton protein, specifically located only in macrophages and microglia. In this study, we explored the contribution of rat Iba1 (+) macrophages in SNL-induced neuropathic pain by using intra-ganglionic injections of naked Iba1-siRNA, delivered at the time the lesion occurred. The results show that 5 days after Iba1 silencing, Iba1 (+) resident macrophages are switched from an M1 (pro-inflammatory) phenotype to an M2 (anti-inflammatory) phenotype, which was confirmed by a significant decrease of M1 markers (CD32 and CD86), a significant increase of M2 markers (CD163 and Arginase-1), a reduced secretion of pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) and an increased release of pro-regenerative factors (BDNF, NGF and NT-3) which initiated the regrowth of adult DRG neurites and reduced SNL-induced neuropathic pain. Our data show for the first time, that it is possible to induce macrophages towards an anti-inflammatory phenotype by interacting with their cytoskeleton.

Traumatic peripheral neuropathic pain is a complex syndrome caused by a primary lesion or dysfunction of the peripheral nervous system. Secondary to the lesion, resident or infiltrating macrophages proliferate and initiate a cross-talk with the sensory neurons, at the level of peripheral nerves and sensory ganglia. The neuron–macrophage interaction, which starts very early after the lesion, is very important for promoting pain development and for initiating changes that will facilitate the chronicization of pain, but it also has the potential to facilitate the resolution of injury-induced changes and, consequently, promote the reduction of pain. This review is an overview of the unique characteristics of nerve-associated macrophages in the peripheral nerves and sensory ganglia and of the molecules and signaling pathways involved in the neuro-immune cross-talk after a traumatic lesion, with the final aim of better understanding how the balance between pro- and anti-nociceptive dialogue between neurons and macrophages may be modulated for new therapeutic approaches.

Extracellular vesicle (EV) preparations have emerged as potentially useful therapeutic tools for various inflammatory or neurodegenerative CNS disorders. Compared to mesenchymal stem cell preparations, they feature enhanced blood–brain barrier permeability and access to injured brain tissue, and better quality assessment and dosing options. A particular case where such therapies may prove beneficial is multiple sclerosis (MS), an autoimmune disease likely triggered by cross-reactivity with some viral antigens, producing an extended demyelinating encephalomyelitis with multiple patchy lesions. Several animal models of MS have been developed, including experimental autoimmune encephalomyelitis (EAE) via injection of myelin oligodendrocyte glycoprotein (MOG) 35–55, inoculation with Theiler’s murine encephalomyelitis virus (TMEV), and the Cuprizone model. Via literature search we retrieved 24 experimental studies on rodent (rat or mouse) MS models with therapeutic administration of native or enhanced EV preparations suitable for this meta-analysis. We found statistically significant mean differences between experimental and control groups for clinical scores (normalized to a 0–5 scale) (−1.21, 95% confidence interval (CI) [−1.49,−0.93] (native EVs); −1.67, CI [−2.28,−1.05] (enhanced EVs)), for pathological scores of inflammation and demyelination, and for several molecular markers of inflammation and myelin repair. These results point to the need for clinical translation of the encouraging preliminary results obtained using such MS animal models.