Triggering receptor expressed on myeloid cells 2 (TREM2) dependent microglial activation promotes cisplatin-induced peripheral neuropathy in mice.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of many antineoplastic agents. Patients treated with chemotherapy often report pain and paresthesias in a "glove-and-stocking" distribution. Diverse mechanisms contribute to the development and maintenance of CIPN. However, the role of spinal microglia in CIPN is not completely understood. In this study, cisplatin-treated mice displayed persistent mechanical allodynia, sensory deficits and decreased density of intraepidermal nerve fibers (IENFs). In the spinal cord, activation of microglia, but not astrocyte, was persistently observed until week five after the first cisplatin injection. Additionally, mRNA levels of inflammation related molecules including IL-1β, IL-6, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS) and CD16, were increased after cisplatin treatment. Intraperitoneal (i.p.) or intrathecal (i.t.) injection with minocycline both alleviated cisplatin-induced mechanical allodynia and sensory deficits, and prevented IENFs loss. Furthermore, cisplatin enhanced triggering receptor expressed on myeloid cells 2 (TREM2) /DNAX-activating protein of 12 kDa (DAP12) signaling in the spinal cord microglia. The blockage of TREM2 by i.t. injecting anti-TREM2 neutralizing antibody significantly attenuated cisplatin-induced mechanical allodynia, sensory deficits and IENFs loss. Meanwhile, anti-TREM2 neutralizing antibody prominently suppressed the spinal IL-6, TNF-α, iNOS and CD16 mRNA level, but it dramatically up-regulated the anti-inflammatory cytokines IL-4 and IL-10. The data demonstrated that cisplatin triggered persistent activation of spinal cord microglia through strengthening TREM2/DAP12 signaling, which further resulted in CIPN. Functional blockage of TREM2 or inhibition of microglia both benefited for cisplatin-induced peripheral neuropathy. Microglial TREM2/DAP12 may serve as a potential target for CIPN intervention.

• Authors: Lang-Yue Hu, Yang Zhou, Wen-Qiang Cui, Xue-Ming Hu, Li-Xia Du, Wen-Li Mi, Yu-Xia Chu, Gen-Cheng Wu, Yan-Qing Wang, Qi-Liang Mao-Ying
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 68 Pg. 132-145 (02 2018) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 29051087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cytokines
• Fcgr3 protein, mouse
• Interleukin-1beta
• Interleukin-6
• Membrane Glycoproteins
• Receptors, IgG
• Receptors, Immunologic
• Trem2 protein, mouse
• Tumor Necrosis Factor-alpha
• Tyrobp protein, mouse
• Interleukin-10
• Interleukin-4
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Minocycline
• Cisplatin

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Astrocytes (metabolism)
• Cisplatin (adverse effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Hyperalgesia (metabolism)
• Interleukin-10 (metabolism)
• Interleukin-1beta (metabolism)
• Interleukin-4 (metabolism)
• Interleukin-6 (metabolism)
• Macrophage Activation
• Male
• Membrane Glycoproteins (metabolism, physiology)
• Mice
• Mice, Inbred C57BL
• Microglia (metabolism, physiology)
• Minocycline (pharmacology)
• Nitric Oxide Synthase Type II (metabolism)
• Pain (metabolism)
• Peripheral Nervous System Diseases (immunology, metabolism)
• Receptors, IgG (metabolism)
• Receptors, Immunologic (metabolism, physiology)
• Signal Transduction
• Spinal Cord (pathology, physiology)
• Tumor Necrosis Factor-alpha (metabolism)