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

• Published in: Brain, behavior, and immunity Vol. 68; pp. 132 - 145
• Main Authors: Hu, Lang-Yue, Zhou, Yang, Cui, Wen-Qiang, Hu, Xue-Ming, Du, Li-Xia, Mi, Wen-Li, Chu, Yu-Xia, Wu, Gen-Cheng, Wang, Yan-Qing, Mao-Ying, Qi-Liang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.02.2018
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Astrocytes - metabolism; Chemotherapeutic neuropathy; Cisplatin; Cisplatin - adverse effects; Cytokines - metabolism; DAP12; Disease Models, Animal; Hyperalgesia - metabolism; Interleukin-10 - metabolism; Interleukin-1beta - metabolism; Interleukin-4 - metabolism; Interleukin-6 - metabolism; Macrophage Activation; Male; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Microglia - metabolism; Microglia - physiology; Microglial activation; Minocycline - pharmacology; Nitric Oxide Synthase Type II - metabolism; Pain - metabolism; Peripheral Nervous System Diseases - immunology; Peripheral Nervous System Diseases - metabolism; Receptors, IgG - metabolism; Receptors, Immunologic - metabolism; Receptors, Immunologic - physiology; Signal Transduction; Spinal Cord - pathology; Spinal Cord - physiology; TREM2; Tumor Necrosis Factor-alpha - metabolism; DAP12; TREM2; Cisplatin; Microglial activation; Chemotherapeutic neuropathy
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2017.10.011

•Cisplatin induced persistent activation of microglia in the spinal cord.•Both i.t. and i.p. injections of microglial inhibitor minocycline attenuated cisplatin-induced CIPN.•I.t. injection of anti-TREM2 antibody alleviated cisplatin-induced CIPN.•Functional blockade of TREM2 suppressed the pro-inflammatory response of microglia. 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.