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1.
Int J Mol Sci ; 24(21)2023 Oct 31.
Article in English | MEDLINE | ID: mdl-37958812

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-1ß) 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.


Subject(s)
Neuralgia , Animals , Rats , Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Ganglia, Spinal/metabolism , Hyperalgesia/metabolism , Macrophages/metabolism , Neuralgia/genetics , Neuralgia/therapy , Spinal Nerves/metabolism
2.
Int J Mol Sci ; 23(20)2022 Oct 16.
Article in English | MEDLINE | ID: mdl-36293246

ABSTRACT

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.


Subject(s)
Neuralgia , Humans , Neuralgia/metabolism , Macrophages/metabolism , Sensory Receptor Cells , Peripheral Nerves , Ganglia, Spinal/metabolism
3.
Cell Mol Neurobiol ; 40(6): 1011-1027, 2020 Aug.
Article in English | MEDLINE | ID: mdl-31950314

ABSTRACT

Iba1 (ionized calcium binding adapter protein 1) is a cytoskeleton protein specific only for microglia and macrophages, where it acts as an actin-cross linking protein. Although frequently regarded as a marker of activation, its involvement in cell migration, membrane ruffling, phagocytosis or in microglia remodeling during immunological surveillance of the brain suggest that Iba1 is not a simple cytoskeleton protein, but a signaling molecule involved in specific signaling pathways. In this study we investigated if Iba1 could also represent a drug target, and tested the hypothesis that its specific silencing with customized Iba1-siRNA can modulate microglia functioning. The results showed that Iba1-silenced BV2 microglia migrate less due to reduced proliferation and cell adhesion, while their phagocytic activity and P2x7 functioning was significantly increased. Our data are the proof of concept that Iba1 protein is a new microglia target, which opens a new therapeutic avenue for modulating microglia behavior.


Subject(s)
Calcium-Binding Proteins/metabolism , Cytoskeletal Proteins/metabolism , Gene Silencing , Microfilament Proteins/metabolism , Microglia/metabolism , Animals , Cell Adhesion , Cell Count , Cell Line , Cell Movement , Cell Proliferation , Leukocyte Common Antigens/metabolism , Mice , Opsonin Proteins/metabolism , Phagocytosis , RNA, Small Interfering/metabolism , Receptors, Purinergic P2X7/metabolism , Reproducibility of Results , Zymosan/metabolism
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