Switching Rat Resident Macrophages from M1 to M2 Phenotype by Iba1 Silencing Has Analgesic Effects in SNL-Induced Neuropathic Pain

Abstract

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.

Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis

“…AIF1 is known to induce the production of pro-inflammatory molecules, including the inflammatory factors IL-6 and TNF-α, and cause elevation of reactive oxygen species (ROS) ( 50 ). Furthermore, it has been shown that the role of AIF1 in macrophages is critical for maintaining their survival and promoting inflammatory activity ( 51 , 52 ). Based on these properties, it is reasonable to assume that there may be a positive correlation between AIF1 and AS, which is an immune-mediated disease characterized by chronic inflammation.…”

Brain-Derived Neurotrophic Factor, Nociception and Pain

“…Similarly, upregulation of BDNF in mast cells was observed following back pain associated with intervertebral disk degeneration [210] and intradiscal inflammatory stimulation induces spinal pain behavior and intervertebral disc degeneration in vivo with an increase of macrophage markers and BDNF (as well as other nociceptive markers) [211]. Furthermore, studies have shown that following various forms of severe sciatic nerve damage, resident macrophages expressing Iba1 protein gather around DRG neurons, thereby exacerbating pain hypersensitivity caused by nerve injury [212]. This study also found that by inhibiting the expression of Iba1 and modifying the characteristics of resident macrophages, specifically shifting them from an M1 to an M2 phenotype, analgesic effects can be achieved in neuropathic pain caused by SNL.…”