4E-BP1–dependent translation in microglia controls mechanical hypersensitivity in male and female mice
Kevin C. Lister, … , Jeffrey S. Mogil, Arkady Khoutorsky
Kevin C. Lister, … , Jeffrey S. Mogil, Arkady Khoutorsky
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e180190. https://doi.org/10.1172/JCI180190.
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Research Article Cell biology Neuroscience

4E-BP1–dependent translation in microglia controls mechanical hypersensitivity in male and female mice

Abstract

Spinal microglia play a pivotal role in the development of neuropathic pain. Peripheral nerve injury induces changes in the transcriptional profile of microglia, including increased expression of components of the translational machinery. Whether microglial protein synthesis is stimulated following nerve injury and has a functional role in mediating pain hypersensitivity is unknown. Here, we show that nascent protein synthesis is upregulated in spinal microglia following peripheral nerve injury in both male and female mice. Stimulating mRNA translation in microglia by selectively ablating the translational repressor eukaryotic initiation factor 4E–binding protein 1 (4E-BP1) promoted the transition of microglia to a reactive state and induced mechanical hypersensitivity in both sexes, whereas spontaneous pain was increased only in males. Conversely, inhibiting microglial translation by expressing a mutant form of 4E-BP1 in microglia attenuated their activation following peripheral nerve injury and alleviated neuropathic pain in both sexes. Thus, stimulating 4E-BP1–dependent translation promotes microglial reactivity and mechanical hypersensitivity, whereas inhibiting it alleviates neuropathic pain.

Authors

Kevin C. Lister, Calvin Wong, Weihua Cai, Sonali Uttam, Patricia Stecum, Rose Rodrigues, Mehdi Hooshmandi, Nicole Brown, Jonathan Fan, Noe Francois-Saint-Cyr, Shannon Tansley, Volodya Hovhannisyan, Diana Tavares-Ferreira, Nikhil Nageshwar Inturi, Khadijah Mazhar, Alain Pacis, Jieyi Yang, Alfredo Ribeiro-da-Silva, Christos G. Gkogkas, Theodore J. Price, Jeffrey S. Mogil, Arkady Khoutorsky

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Figure 2

Increase in microglial translation induces mechanical pain hypersensitivity.

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Increase in microglial translation induces mechanical pain hypersensitiv...
(A) Schematic illustration depicting regulation of mRNA translation via the mTORC1/4E-BP1 axis. (B) Generation of mice with conditional ablation of 4E-BP1 in microglia under the TMEM119CreERT2 promoter. (C) IHC against 4E-BP1 confirmed reduced levels of 4E-BP1 in 4E-BP1–cKO mice (n = 3 mice/group). Scale bar: 20 μm. Yellow arrows mark the location of microglia. Control (TMEM119CreERT2) and 4E-BP1–cKO mice were tested for mechanical and thermal sensitivity. Mechanical sensitivity was tested using von Frey (males in D and females in F) and tail-clip (males in E and females in G) assays. Thermal sensitivity was tested using radiant heat paw-withdrawal (males in H and females in J) and hot-plate (males in I and females in K) assays. Spontaneous pain was assessed using the mouse grimace scale (MGS; males in L and females in M). In behavioral experiments, n = 7–10 mice per group. For analyses, unpaired 2-tailed t test was used. Two-way ANOVA was used to assess sex differences in the MGS test (L and M), revealing a significant main effect of sex [F(1,24) = 6.548, P = 0.0172]. Tukey’s multiple-comparison test showed a difference between control and 4E-BP1–cKO males (P = 0.0041), but not between females (P = 0.8575). Data are plotted as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001.