Macrophage-Colony Stimulating Factor Derived from Injured Primary Afferent Induces Proliferation of Spinal Microglia and Neuropathic Pain in Rats.

Masamichi Okubo,Hideshi Yagi,Hiroki Yamanaka,Hirosato Kanda,Yi Dai,Kimiko Kobayashi,Koichi Noguchi,Simon Beggs

doi:10.1371/journal.pone.0153375

Masamichi Okubo, Hideshi Yagi + Show 6 more

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https://doi.org/10.1371/journal.pone.0153375

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Abstract

Peripheral nerve injury induces proliferation of microglia in the spinal cord, which can contribute to neuropathic pain conditions. However, candidate molecules for proliferation of spinal microglia after injury in rats remain unclear. We focused on the colony-stimulating factors (CSFs) and interleukin-34 (IL-34) that are involved in the proliferation of the mononuclear phagocyte lineage. We examined the expression of mRNAs for macrophage-CSF (M-CSF), granulocyte macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF) and IL-34 in the dorsal root ganglion (DRG) and spinal cord after spared nerve injury (SNI) in rats. RT-PCR and in situ hybridization revealed that M-CSF and IL-34, but not GM- or G-CSF, mRNAs were constitutively expressed in the DRG, and M-CSF robustly increased in injured-DRG neurons. M-CSF receptor mRNA was expressed in naive rats and increased in spinal microglia following SNI. Intrathecal injection of M-CSF receptor inhibitor partially but significantly reversed the proliferation of spinal microglia and in early phase of neuropathic pain induced by SNI. Furthermore, intrathecal injection of recombinant M-CSF induced microglial proliferation and mechanical allodynia. Here, we demonstrate that M-CSF is a candidate molecule derived from primary afferents that induces proliferation of microglia in the spinal cord and leads to induction of neuropathic pain after peripheral nerve injury in rats.

Highlights

Microglia colonizes the central nervous system during development, originating from hematopoietic stem cells found in yolk sac [1]and accounts for 5–20% of the glial cell population in the adult brain [2]
We examined whether induction of M-colony-stimulating factors (CSFs) in injured-primary afferent neurons contributes to the proliferation and activation of spinal microglia in vivo and that macrophage-colony stimulating factor (M-CSF)/M-CSF receptor (M-CSFr) signaling leads to generation of neuropathic pain after peripheral nerve injury using different methods and species that were used by Guan et al [19]
Iba1 positive cells were heavily colocalized with ki67 and p-p38 in the spinal dorsal horn at 2 days after spared nerve injury (SNI) (Fig 4D and 4E). These results suggest that M-CSFr is involved in microglial proliferation in the spinal cord and the early phase of neuropathic pain after peripheral nerve injury

Summary

Introduction

Microglia colonizes the central nervous system during development, originating from hematopoietic stem cells found in yolk sac [1]and accounts for 5–20% of the glial cell population in the adult brain [2]. Microglia play a role in both physiological and pathological conditions. Paolice et al demonstrated that microglia are involved in synaptic pruning of excessive synapses in the developing brain [3]. M-CSF from Injured DRG Induces Microglia and Pain PLOS ONE | DOI:10.1371/journal.pone.0153375 April 12, 2016

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