CNS myeloid cells critically regulate heat hyperalgesia
Stefanie Kälin, … , Christian Witzel, Frank L. Heppner
Stefanie Kälin, … , Christian Witzel, Frank L. Heppner
Published July 2, 2018; First published April 10, 2018
Citation Information: J Clin Invest. 2018;128(7):2774-2786. https://doi.org/10.1172/JCI95305.
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Research Article Neuroscience

CNS myeloid cells critically regulate heat hyperalgesia

Abstract

Activation of non-neuronal microglia is thought to play a causal role in spinal processing of neuropathic pain. To specifically investigate microglia-mediated effects in a model of neuropathic pain and overcome the methodological limitations of previous approaches exploring microglia function upon nerve injury, we selectively ablated resident microglia by intracerebroventricular ganciclovir infusion into male CD11b-HSVTK–transgenic mice, which was followed by a rapid, complete, and persistent (23 weeks) repopulation of the CNS by peripheral myeloid cells. In repopulated mice that underwent sciatic nerve injury, we observed a normal response to mechanical stimuli, but an absence of thermal hypersensitivity ipsilateral to the injured nerve. Furthermore, we found that neuronal expression of calcitonin gene–related peptide (CGRP), which is a marker of neurons essential for heat responses, was diminished in the dorsal horn of the spinal cord in repopulated mice. These findings identify distinct mechanisms for heat and mechanical hypersensitivity and highlight a crucial contribution of CNS myeloid cells in the facilitation of noxious heat.

Authors

Stefanie Kälin, Kelly R. Miller, Roland E. Kälin, Marina Jendrach, Christian Witzel, Frank L. Heppner

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Figure 2

Repopulation in GFP>TK animals.

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Repopulation in GFP>TK animals. (A) Confocal microscopic analysis (me...
(A) Confocal microscopic analysis (merged image) of peripherally derived myeloid cells in the lumbar spinal cord revealed that almost all GFP+ cells (green) were also Iba1+ (red) after microglia depletion. Scale bar: 500 μm. Inset, original magnification, ×40. (B and C) Quantitative stereological analysis of total Iba1+ and GFP+ cells in the contralateral lumbar spinal cord of GFP>TK mice treated with GCV, either continuously (n = 8) or short term (n = 10), revealed a 75% and 92% repopulation with peripheral myeloid cells, respectively, whereas their corresponding GFP>WT littermates (continuous GCV treatment, n = 10; short-term GCV treatment, n = 9) showed an average of only 10% GFP+ cells. (D and E) Vehicle-treated (aCSF-treated) (n = 8/genotype) as well as nontreated GFP>WT (n = 9) and GFP>TK (n = 4) mice showed only moderate infiltration of peripheral myeloid cells. The dashed line and green asterisks are shown for comparison of GFP+ cells. Error bars indicate the SEM. *P < 0.05 and ***P < 0.001, by paired, 2-tailed Student’s t test for corresponding GFP>WT and GFP>TK pairs.