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Neuropathic pain remains poorly managed by current therapies, highlighting the need to improve our knowledge of chronic pain mechanisms. In neuropathic pain models, dorsal root ganglia (DRG) nociceptive neurons transfer miR-21 packaged in extracellular vesicles to macrophages that promote a proinflammatory phenotype and contribute to allodynia. Here we show that miR-21 conditional deletion in DRG neurons was coupled with lack of upregulation of chemokine CCL2 after nerve injury and reduced accumulation of CCR2-expressing macrophages, which showed TGF-ß-related pathway activation and acquired an M2-like antinociceptive phenotype. Indeed, neuropathic allodynia was attenuated after conditional knockout of miR21 and restored by TGF-ßR inhibitor (SB431542) administration. Since TGF-ßR2 and TGF-ß1 are known miR-21 targets, we suggest that miR-21 transfer from injured neurons to macrophages maintains a proinflammatory phenotype via suppression of such an antiinflammatory pathway. These data support miR-21 inhibition as a possible approach to maintain polarization of DRG macrophages at an M2-like state and attenuate neuropathic pain.
Introduction
Peripheral neuropathy is a debilitating condition that often leads to severe and chronic neuropathic pain, for which novel treatment strategies are needed because current drugs have limited efficacy and severe side effects (1, 2). In neuropathic pain states, neuronal activity at the site of nerve injury, in dorsal root ganglia (DRGs), and the dorsal horn of the spinal cord provokes immune system responses. Thus, central and peripheral sensitizations are facilitated by microglia, the resident immune cells of the CNS, and monocytes/macrophages in the PNS, respectively (3, 4).
Macrophages are a diverse cell population that exhibits remarkable plasticity after injury and disease and expresses specific hallmarks of their tissue of residence (5-7). Besides a primary function in host defense and inflammatory response, macrophages can release mediators, such as cytokines, that sensitize sensory neurons and contribute to neuropathic pain mechanisms (8). Specifically, after peripheral nerve injury, sensory neuronassociated macrophages (sNAMs) accumulate in lumbar DRGs and at the site of nerve injury (9-11), and play a mechanistic role, as monocyte/macrophage depletion prevents neuropathic pain-like behavior (12, 13). In response to peripheral axon injury, sensory neuron cell bodies upregulate chemokines such as CCL2, which promotes infiltration of monocytes/macrophages in DRGs (14, 15) through the satellite cell sheath around the primary sensory neuron in an attempt to clear damaged neurons (16, 17). Hence, blood-derived...