Spinal Microgliosis Due to Resident Microglial Proliferation Is Required for Pain Hypersensitivity after Peripheral Nerve Injury

• Published in: Cell reports (Cambridge) Vol. 16; no. 3; pp. 605 - 614
• Main Authors: Gu, Nan, Peng, Jiyun, Murugan, Madhuvika, Wang, Xi, Eyo, Ukpong B., Sun, Dongming, Ren, Yi, DiCicco-Bloom, Emanuel, Young, Wise, Dong, Hailong, Wu, Long-Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.07.2016; Elsevier
• Subjects: Animals; Cell Proliferation - physiology; Chemokine CX3CL1 - metabolism; CX3C Chemokine Receptor 1 - metabolism; Disease Models, Animal; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Mice, Inbred C57BL; Microglia - metabolism; Microglia - pathology; Monocytes - metabolism; Monocytes - pathology; Neuralgia - metabolism; Neuralgia - pathology; Pain Measurement - methods; Peripheral Nerve Injuries - metabolism; Peripheral Nerve Injuries - pathology; Receptors, Purinergic P2Y12 - metabolism; Spinal Cord Dorsal Horn - metabolism; Spinal Cord Dorsal Horn - pathology; Spinal Nerves - metabolism; Spinal Nerves - pathology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.06.018

Peripheral nerve injury causes neuropathic pain accompanied by remarkable microgliosis in the spinal cord dorsal horn. However, it is still debated whether infiltrated monocytes contribute to injury-induced expansion of the microglial population. Here, we found that spinal microgliosis predominantly results from local proliferation of resident microglia but not from infiltrating monocytes after spinal nerve transection (SNT) by using two genetic mouse models (CCR2RFP/+:CX3CR1GFP/+ and CX3CR1creER/+:R26tdTomato/+ mice) as well as specific staining of microglia and macrophages. Pharmacological inhibition of SNT-induced microglial proliferation correlated with attenuated neuropathic pain hypersensitivities. Microglial proliferation is partially controlled by purinergic and fractalkine signaling, as CX3CR1−/− and P2Y12−/− mice show reduced spinal microglial proliferation and neuropathic pain. These results suggest that local microglial proliferation is the sole source of spinal microgliosis, which represents a potential therapeutic target for neuropathic pain management. [Display omitted] •Peripheral nerve injury causes spinal microgliosis due to microglial proliferation•Peripheral monocytes do not infiltrate into the dorsal horn after nerve injury•Inhibition of spinal microgliosis attenuates neuropathic pain hypersensitivity•Purinergic and fractalkine signaling control injury-induced microglial proliferation Gu et al. show that resident microglial proliferation is the major contributor to microgliosis in the spinal dorsal horn after peripheral nerve injury. However, there is no monocyte infiltration associated with injury-induced microgliosis in the dorsal horn. Pharmacological or genetic inhibition of microglial proliferation attenuates neuropathic pain hypersensitivity.